Pharmaceutical compositions comprising dextromethorphan and quinidine for the treatment of neurological disorders

ABSTRACT

Pharmaceutical compositions and methods for treating neurological disorders by administering same are provided. The compositions comprise dextromethorphan in combination with quinidine.

RELATED APPLICATION

This application is a continuation, under 35 U.S.C. §120, ofInternational Patent Application No. PCT/US2003/022303, filed on Jul.17, 2003 under the Patent Cooperation Treaty (PCT), which was publishedby the International Bureau in English on Jan. 22, 2004, whichdesignates the United States and claims the benefit of U.S. ProvisionalApplication No. 60/396,661, filed Jul. 17, 2002.

FIELD OF THE INVENTION

Pharmaceutical compositions and methods for treating neurologicaldisorders are provided. The compositions comprise dextromethorphan incombination with quinidine.

BACKGROUND OF THE INVENTION

Patients suffering from neurodegenerative diseases or brain damage suchas is caused by stroke or head injury often are afflicted with emotionalproblems associated with the disease or injury. The terms emotionallability and pseudobulbar affect are used by psychiatrists andneurologists to refer to a set of symptoms that are often observed inpatients who have suffered a brain insult such as a head injury, stroke,brain tumor, or encephalitis, or who are suffering from a progressiveneurodegenerative disease such as Amyotrophic Lateral Sclerosis (ALS,also called motor neuron disease or Lou Gehrig's disease), Parkinson'sdisease, Alzheimer's disease, or multiple sclerosis. In the greatmajority of such cases, emotional lability occurs in patients who havebilateral damage (damage which affects both hemispheres of the brain)involving subcortical forebrain structures.

Emotional lability, which is distinct from clinical forms of reactive orendogenous depression, is characterized by intermittent spasmodicoutbursts of emotion (usually manifested as intense or even explosivecrying or laughing) at inappropriate times or in the absence of anyparticular provocation. Emotional lability or pseudobulbar affect isalso referred to by the terms emotionalism, emotional incontinence,emotional discontrol, excessive emotionalism, and pathological laughingand crying. The feelings that accompany emotional lability are oftendescribed in words such as “disconnectedness,” since patients are fullyaware that an outburst is not appropriate in a particular situation, butthey do not have control over their emotional displays.

Emotional lability or pseudobulbar affect becomes a clinical problemwhen the inability to control emotional outbursts interferes in asubstantial way with the ability to engage in family, personal, orbusiness affairs. For example, a businessman suffering from early-stageALS or Parkinson's disease might become unable to sit through businessmeetings, or a patient might become unable to go out in public, such asto a restaurant or movie, due to transient but intense inability to keepfrom crying or laughing at inappropriate times in front of other people.These symptoms can occur even though the patient still has more thanenough energy and stamina to do the physical tasks necessary to interactwith other people. Such outbursts, along with the feelings of annoyance,inadequacy, and confusion that they usually generate and the visibleeffects they have on other people, can severely aggravate the othersymptoms of the disease; they lead to feelings of ostracism, alienation,and isolation, and they can render it very difficult for friends andfamily members to provide tolerant and caring emotional support for thepatient.

SUMMARY OF THE INVENTION

There remains a need for additional or improved forms of treatment foremotional lability and other chronic disorders, such as chronic pain.Such a treatment preferably provides at least some degree of improvementcompared to other known drugs, in at least some patients. A method fortreating emotional lability in at least some patients suffering fromneurologic impairment, such as a progressive neurologic disease, isdesirable.

A method of treating emotional lability, pseudobulbar affect, and otherchronic conditions in human patients who are in need of such treatment,without oversedation or otherwise significantly interfering withconsciousness or alertness is provided. The treatment involvesadministering dextromethorphan in combination with a minimum dosage ofquinidine.

In a first embodiment, a method for treating pseudobulbar affect oremotional lability is provided, the method including administering to apatient in need thereof dextromethorphan in combination with quinidine,wherein an amount of dextromethorphan administered includes from about20 mg/day to about 200 mg/day, and wherein an amount of quinidineadministered includes from about 10 mg/day to less than about 50 mg/day.

In an aspect of the first embodiment, the pseudobulbar affect oremotional lability is caused by a neurodegenerative disease or conditionor a brain injury.

In a second embodiment, a method for treating neuropathic pain isprovided, the method including administering to a patient in needthereof dextromethorphan in combination with quinidine, wherein anamount of dextromethorphan administered includes from about 20 mg/day toabout 200 mg/day, and wherein an amount of quinidine administeredincludes from about 10 mg/day to less than about 50 mg/day.

In a third embodiment, a method for treating a neurodegenerative diseaseor condition is provided, the method including administering to apatient in need thereof dextromethorphan in combination with quinidine,wherein an amount of dextromethorphan administered includes from about20 mg/day to about 200 mg/day, and wherein an amount of quinidineadministered includes from about 10 mg/day to less than about 50 mg/day.

In an aspect of the third embodiment, the neurodegenerative disease orcondition is selected from the group consisting of amyotrophic lateralsclerosis, multiple sclerosis, Parkinson's disease, and Alzheimer'sdisease.

In a fourth embodiment, a method for treating a brain injury isprovided, the method including administering to a patient in needthereof dextromethorphan in combination with quinidine, wherein anamount of dextromethorphan administered includes from about 20 mg/day toabout 200 mg/day, and wherein an amount of quinidine administeredincludes from about 10 mg/day to less than about 50 mg/day.

In an aspect of the fourth embodiment, the brain injury is selected fromthe group consisting of stroke, traumatic brain injury, ischemic event,hypoxic event, and neuronal death.

In aspects of the first through fourth embodiments, the dextromethorphanand the quinidine are administered as one combined dose per day.

In aspects of the first through fourth embodiments, the dextromethorphanand the quinidine are administered as at least two combined doses perday.

In aspects of the first through fourth embodiments, the amount ofquinidine administered includes from about 20 mg/day to about 45 mg/day.

In aspects of the first through fourth embodiments, the amount ofdextromethorphan administered includes from about 20 mg/day to about 60mg/day.

In aspects of the first through fourth embodiments, at least one of thequinidine and the dextromethorphan is in a form of a pharmaceuticallyacceptable salt.

In aspects of the first through fourth embodiments, the pharmaceuticallyacceptable salt is selected from the group consisting of salts of alkalimetals, salts of lithium, salts of sodium, salts of potassium, salts ofalkaline earth metals, salts of calcium, salts of magnesium, salts oflysine, salts of N,N′-dibenzylethylenediamine, salts of chloroprocaine,salts of choline, salts of diethanolamine, salts of ethylenediamine,salts of meglumine, salts of procaine, salts of tris, salts of freeacids, salts of free bases, inorganic salts, salts of sulfate, salts ofhydrochloride, and salts of hydrobromide.

In aspects of the first through fourth embodiments, the quinidineincludes quinidine sulfate and the dextromethorphan includesdextromethorphan hydrobromide, and wherein an amount of quinidinesulfate administered includes from about 30 mg/day to 60 mg/day andwherein an amount of dextromethorphan hydrobromide administered includesfrom about 30 mg/day to about 60 mg/day.

In a fifth embodiment, a method for treating pseudobulbar affect oremotional lability is provided, the method including administering to apatient in need thereof dextromethorphan in combination with quinidine,wherein the dextromethorphan and the quinidine are administered in acombined dose, and wherein a weight ratio of dextromethorphan toquinidine in the combined dose is about 1:1.25 or less.

In an aspect of the fifth embodiment, the pseudobulbar affect oremotional lability is caused by a neurodegenerative disease or conditionor a brain injury.

In a sixth embodiment, a method for treating neuropathic pain isprovided, the method including administering to a patient in needthereof dextromethorphan in combination with quinidine, wherein thedextromethorphan and the quinidine are administered in a combined dose,and wherein a weight ratio of dextromethorphan to quinidine in thecombined dose is about 1:1.25 or less.

In a seventh embodiment, a method for treating a neurodegenerativedisease or condition is provided, the method including administering toa patient in need thereof dextromethorphan in combination withquinidine, wherein the dextromethorphan and the quinidine areadministered in a combined dose, and wherein a weight ratio ofdextromethorphan to quinidine in the combined dose is about 1:1.25 orless.

In an aspect of the seventh embodiment, the neurodegenerative disease orcondition is selected from the group consisting of amyotrophic lateralsclerosis, multiple sclerosis, Parkinson's disease, and Alzheimer'sdisease.

In an eighth embodiment, a method for treating a brain injury isprovided, the method including administering to a patient in needthereof dextromethorphan in combination with quinidine, wherein thedextromethorphan and the quinidine are administered in a combined dose,and wherein a weight ratio of dextromethorphan to quinidine in thecombined dose is about 1:1.25 or less.

In an aspect of the eighth embodiment, the brain injury is selected fromthe group consisting of stroke, traumatic brain injury, ischemic event,hypoxic event, and neuronal death.

In aspects of the fifth through eighth embodiments, the weight ratio ofdextromethorphan to quinidine in the combined dose is about 1:0.75 orless.

In aspects of the fifth through eighth embodiments, the amount ofquinidine administered includes from about 20 mg/day to about 45 mg/day,and wherein the amount of dextromethorphan administered includes fromabout 20 mg/day to about 60 mg/day.

In aspects of the fifth through eighth embodiments, at least one of thequinidine and the dextromethorphan is in a form of a pharmaceuticallyacceptable salt.

In aspects of the fifth through eighth embodiments, the pharmaceuticallyacceptable salt is selected from the group consisting of salts of alkalimetals, salts of lithium, salts of sodium, salts of potassium, salts ofalkaline earth metals, salts of calcium, salts of magnesium, salts oflysine, salts of N,N′-dibenzylethylenediamine, salts of chloroprocaine,salts of choline, salts of diethanolamine, salts of ethylenediamine,salts of meglumine, salts of procaine, salts of tris, salts of freeacids, salts of free bases, inorganic salts, salts of sulfate, salts ofhydrochloride, and salts of hydrobromide.

In aspects of the fifth through eighth embodiments, the quinidineincludes quinidine sulfate and the dextromethorphan includesdextromethorphan hydrobromide, and wherein an amount of quinidinesulfate administered includes from about 30 mg/day to about 60 mg/dayand wherein an amount of dextromethorphan hydrobromide administeredincludes from about 30 mg/day to about 60 mg/day.

In aspects of the fifth through eighth embodiments, one combined dose isadministered per day.

In aspects of the fifth through eighth embodiments, two or more combineddoses are administered per day.

In a ninth embodiment, a pharmaceutical composition suitable for use intreating pseudobulbar affect or emotional lability is provided, thecomposition including a tablet or a capsule, the tablet or capsuleincluding dextromethorphan and quinidine, wherein a weight ratio ofdextromethorphan to quinidine is about 1:1.25 or less.

In an aspect of the ninth embodiment, the pseudobulbar affect oremotional lability is caused by a neurodegenerative disease or conditionor a brain injury.

In a tenth embodiment, a pharmaceutical composition suitable for use intreating neuropathic pain is provided, the composition including atablet or a capsule, the tablet or capsule including dextromethorphanand quinidine, wherein a weight ratio of dextromethorphan to quinidineis about 1:1.25 or less.

In an eleventh embodiment, a pharmaceutical composition suitable for usein treating a neurodegenerative disease or condition is provided, thecomposition including a tablet or a capsule, the tablet or capsuleincluding dextromethorphan and quinidine, wherein a weight ratio ofdextromethorphan to quinidine is about 1:1.25 or less.

In an aspect of the eleventh embodiment, the neurodegenerative diseaseor condition is selected from the group consisting of amyotrophiclateral sclerosis, multiple sclerosis, Parkinson's disease, andAlzheimer's disease.

In a twelfth embodiment, a pharmaceutical composition suitable for usein a brain injury is provided, the composition including a tablet or acapsule, the tablet or capsule including dextromethorphan and quinidine,wherein a weight ratio of dextromethorphan to quinidine is about 1:1.25or less.

In an aspect of the twelfth embodiment, the brain injury is selectedfrom the group consisting of stroke, traumatic brain injury, ischemicevent, hypoxic event, and neuronal death.

In aspects of the ninth through twelfth embodiments, the weight ratio ofdextromethorphan to quinidine is about 1:0.75 or less.

In aspects of the ninth through twelfth embodiments, the quinidine ispresent in an amount of from about 20 mg to about 45 mg, and wherein thedextromethorphan is present in an amount of from about 20 mg to about 60mg.

In aspects of the ninth through twelfth embodiments, at least one of thequinidine and the dextromethorphan is in a form of a pharmaceuticallyacceptable salt.

In aspects of the ninth through twelfth embodiments, thepharmaceutically acceptable salt is selected from the group consistingof salts of alkali metals, salts of lithium, salts of sodium, salts ofpotassium, salts of alkaline earth metals, salts of calcium, salts ofmagnesium, salts of lysine, salts of N,N′-dibenzylethylenediamine, saltsof chloroprocaine, salts of choline, salts of diethanolamine, salts ofethylenediamine, salts of meglumine, salts of procaine, salts of his,salts of free acids, salts of free bases, inorganic salts, salts ofsulfate, salts of hydrochloride, and salts of hydrobromide.

In aspects of the ninth through twelfth embodiments, the quinidineincludes quinidine sulfate and the dextromethorphan includesdextromethorphan hydrobromide, wherein the quinidine sulfate is presentin an amount of from about 30 mg to about 60 mg, and wherein thedextromethorphan hydrobromide is present in an amount of from about 30mg to about 60 mg.

In a thirteenth embodiment, use of dextromethorphan and quinidine in thepreparation of a medicament for treating pseudobulbar affect oremotional lability is provided, wherein the medicament includes acapsule or a tablet, and wherein dextromethorphan and quinidine arepresent in the capsule or tablet at a weight ratio of dextromethorphanto quinidine of 1:1.25 or less.

In an aspect of the thirteenth embodiment, the pseudobulbar affect oremotional lability is caused by a neurodegenerative disease or conditionor a brain injury.

In a fourteenth embodiment, use of dextromethorphan and quinidine in thepreparation of a medicament for treating neuropathic pain is provided,wherein the medicament includes a capsule or a tablet, and whereindextromethorphan and quinidine are present in the capsule or tablet at aweight ratio of dextromethorphan to quinidine of 1:1.25 or less.

In a fifteenth embodiment, use of dextromethorphan and quinidine in thepreparation of a medicament for treating a neurodegenerative disease orcondition is provided, wherein the medicament includes a capsule or atablet, and wherein dextromethorphan and quinidine are present in thecapsule or tablet at a weight ratio of dextromethorphan to quinidine of1:1.25 or less.

In an aspect of the fifteenth embodiment, the neurodegenerative diseaseor condition is selected from the group consisting of amyotrophiclateral sclerosis, multiple sclerosis, Parkinson's disease, andAlzheimer's disease.

In a sixteenth embodiment, use of dextromethorphan and quinidine in thepreparation of a medicament for treating a brain injury is provided,wherein the medicament includes a capsule or a tablet, and whereindextromethorphan and quinidine are present in the capsule or tablet at aweight ratio of dextromethorphan to quinidine of 1:1.25 or less.

In an aspect of the sixteenth embodiment, the brain injury is selectedfrom the group consisting of stroke, traumatic brain injury, ischemicevent, hypoxic event, and neuronal death.

In aspects of the thirteenth through sixteenth embodiments,dextromethorphan and quinidine are present in the capsule or tablet at aweight ratio of dextromethorphan to quinidine of 1:0.75 or less.

In aspects of the thirteenth through sixteenth embodiments, at least oneof the quinidine and the dextromethorphan is in a form of apharmaceutically acceptable salt.

In aspects of the thirteenth through sixteenth embodiments, thepharmaceutically acceptable salt is selected from the group consistingof salts of alkali metals, salts of lithium, salts of sodium, salts ofpotassium, salts of alkaline earth metals, salts of calcium, salts ofmagnesium, salts of lysine, salts of N,N′-dibenzylethylenediamine, saltsof chloroprocaine, salts of choline, salts of diethanolamine, salts ofethylenediamine, salts of meglumine, salts of procaine, salts of tris,salts of free acids, salts of free bases, inorganic salts, salts ofsulfate, salts of hydrochloride, and salts of hydrobromide.

In aspects of the thirteenth through sixteenth embodiments, thequinidine includes quinidine sulfate and the dextromethorphan includesdextromethorphan hydrobromide, wherein the quinidine sulfate is presentin an amount of from about 30 mg to about 60 mg, and wherein thedextromethorphan hydrobromide is present in an amount of from about 30mg to about 60 mg.

In aspects of the thirteenth through sixteenth embodiments, thequinidine is present in an amount of from about 20 mg to about 45 mg,and wherein the dextromethorphan is present in an amount of from about20 mg to about 60 mg.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a box plot of CNS-LS scores for Clinical Study #4. Thedistributions of CNS-LS scores are symmetrical and contain only oneoutlier. These distributions support the use of ANCOVA for the analysisof the CNS-LS scores. As prospectively specified in the study protocol,the differences in mean improvement in CNS-LS cores, adjusted for centerand baseline CNS-LS scores, were analyzed by using linear regressionaccording to the ANCOVA method of Frison and Pocock. The results of thisanalysis are in Table 30. The results of the additional analyses withoutany adjustments or with an adjustment for baseline CNS-LS score aloneare also in this table.

FIG. 2 provides a plot depicting adjusted mean reductions in CNS-LSscores for the three treatment groups from the primary efficacy analysisof the ITT population of Clinical Study #4. Reductions in CNS-LS scoresbelow the horizontal lines are statistically significantly differentfrom 30DM/30Q at the significance levels indicated.

FIG. 3 provides the disposition of subjects by MTD group participatingin Clinical Study #5.

FIG. 4 depicts Mean Sleep Ratings from the Subject Diaries of subjectsparticipating in Clinical Study #5.

FIG. 5. Mean Present Pain Intensity Ratings from the Subject Diaries ofsubjects participating in Clinical Study #5.

FIG. 6. Mean Activity Ratings from the Subject Diaries of subjectsparticipating in Clinical Study #5.

FIG. 7. Mean Pain Ratings from the Subject Diaries of subjectsparticipating in Clinical Study #5.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following description and examples illustrate a preferred embodimentof the present invention in detail. Those of skill in the art willrecognize that there are numerous variations and modifications of thisinvention that are encompassed by its scope. Accordingly, thedescription of a preferred embodiment should not be deemed to limit thescope of the present invention.

Emotional lability or pseudobulbar affect is associated with a number ofneurological diseases, such as stroke (House et al., BMJ, 1989;298:991-4), multiple sclerosis (MS) (Cotrell et al., J. Neurol.Psychopathol., 1926; 7:1-30; Feinstein et al., Arch. Neurol., 1997;54:1116-21), amyotrophic lateral sclerosis (ALS) (Miller et al.,Neurol., 1999; 52:1311-23; Jackson et al., Semin. Neurol. 1998;18:27-39; Poeck, K., Pathophysiology of emotional disorders associatedwith brain damage. In: P. J. Vinken, G. W. Bruyn, editors. Handbook ofClinical Neurology. Amsterdam: North-Holland Publishing Company 1969;pp. 343-67), Alzheimer's disease (Starkstein et al., J. Neurol.Neurosurg. Psychiatry, 1995; 59:55-64), and traumatic brain injury(Brooks, N., Acta Neurochirurgica Suppl., 44 1988; 59-64). Studies havesuggested that pseudobulbar affect occurs in up to 50% of patients withALS (Gallagher, J. P., Acta Neurol. Scand. 1989; 80:114-7).

Emotional lability or pseudobulbar affect in the context of neurologicalinjury can be considered a disconnection syndrome resulting from loss ofcortical communication with the brainstem or cerebellum Wilson S A K, J.Neurol. Psychopathol., 1924; IV:299-333; Parvivzi et al., Brain, 2001;124:1708-19). At the neurotransmitter level, disruptions of ascendingand descending serotonergic pathways arising in the brainstem, anddysregulation of dopaminergic projections to the striatum and cortexhave been implicated (Andersen et al., Stroke, 1994; 25:1050-2; Ross etal., J. Nerv. Ment. Dis., 1987; 175:165-72; Shaw et al., Brain Sciencesin Psychiatry, London: Butterworth, 1982; Udaka et al., Arch. Neurol.1984; 41:1095-6).

A body of evidence suggests that pseudobulbar affect can be modulatedthrough pharmacologic intervention. In 1979, Wolf reported that levodopawas effective in subjects with pathological laughing (Wolf et al.,Neurol., 1979; 29:1435-6.). However, in a follow-up study, only 10 of 25subjects responded satisfactorily to treatment (Udaka et al., Arch.Neurol., 1984; 41:1095-6). There have been reports of symptomaticbenefit with other drugs, including amantadine, imipramine, desipramine,nortriptyline, amitriptyline, sertraline, fluoxetine, levodopa,methylphenidate, and thyrotropin-releasing hormone (Dark et al., Austr.N. Zeal. J. Psychiatry, 1996; 30:472-9; Iannoccone et al., Clin.Neuropharm., 1996; 19:532-5).

The best previously known therapies for treating emotional labilityinvolve the drugs amitriptyline, amantadine, and levodopa. Althoughreports such as Udaka et al., Arch. Neurol. 1984, 41: 1095-1096, andSchiffer et al., N. Engl. J. Med. 1985, 312: 1480-1482 indicate thatthese compounds may be effective in helping reduce pathological displaysof emotion in some patients, they make it clear that none of these priorart drugs are effective in all patients, and even in patients whoreceive some benefit, the effect usually stops far short of an effectivecure. A common practice for many clinical neurologists is to prescribeamitriptyline and amantadine, one at a time, in the hope that one ofthem might be able to provide any level of improvement in the patient'scondition. However, all both fall short of offering an effective cure.In addition, levodopa is not satisfactory, since it has other effectsand is a relatively powerful drug.

ALS is a neurodegenerative disease produced by progressive loss of upperand lower motor neurons. Up to 50 percent of patients with ALS exhibitemotional lability, and it is more prevalent in those with the bulbarform of ALS (Gallagher J P, Acta Neurol. Scand., 1989; 80:114-7). Basedon the notion that excitotoxicity secondary to impaired recycling ofglutamate may be a factor in the etiology of ALS, riluzole, a glutamaterelease inhibitor, has been used to treat ALS (Jerusalem et al.,Neurology, 1996; 47:S218-20; Doble A., Neurology, 1996; 47:S233-41).Riluzole modestly extends life span but does not confer symptomaticbenefit (Bensimon et al., N. Eng. J. Med., 1994; 330:585-91; KwiecinskiH, Neurol. Neurochir. Pol., 2001; 35:51-9).

Because of the possibility that an excitotoxic process involvingglutamate is etiologically implicated in ALS, several investigators haveattempted to modify or arrest the course of ALS by the administration ofdextromethorphan (DM). DM is an noncompetitive antagonist of theN-methyl-D-aspartate-sensitive ionotropic glutamate receptor, and itacts by reducing the level of excitatory activity. However, DM isextensively metabolized to dextrorphan (DX) and a number of othermetabolites. Cytochrome P450 2D6 (CYP2D6) is the key enzyme responsiblefor the formation of DX from DM. A subset of the population, 5 to 10% ofCaucasians, has reduced activity of this enzyme (Hildebrand et al., Eur.J. Clin. Pharmacol., 1989; 36:315-318). Such individuals are referred toas “poor metabolizers” of DM in contrast to the majority of individualswho are referred to as “extensive metabolizers” of DM (Vetticaden etal., Pharm. Res., 1989; 6:13-9).

A number of in vitro studies have been undertaken to determine the typesof drugs that inhibit CYP2D6 activity. Quinidine (O) is one of the mostpotent of those that have been studied (Inaba et al., Br. J. Clin.Pharmacol., 1986; 22:199-200). These observations led to the hypothesisthat concomitant dosing with Q could increase the concentration of DM inplasma.

A number of chronic disorders other than emotional lability also havesymptoms which are known to be very difficult to treat, and often failto respond to safe, non-addictive, and non-steroid medications.Disorders such as intractable coughing fail to respond to conventionalmedicines and are typically treated by such drugs as codeine, morphine,or the anti-inflammatory steroid prednisone. These drugs areunacceptable for long-term treatment due to dangerous side effects,long-term risks to the patient's health, or the danger of addiction.There has been no satisfactory treatment for the severe itching and rashassociated with dermatitis. Drugs such as prednisone and even tricyclicantidepressants, as well as topical applications have been employed, butdo not appear to offer substantial and consistent relief. Chronic paindue to conditions such as stroke, cancer, and trauma, as well asneuropathic pain resulting from conditions such as diabetes and shingles(herpes zoster), for example, is also a problem which resists treatment.Neuropathic pain includes, for example, diabetic neuropathy,postherpetic neuralgia, phantom limb pain, trigeminal neuralgia, andsciatica. Postherpetic neuralgia (PHN) is a complication of shingles andoccurs in approximately ten percent of patients with herpes zoster. Theincidence of PHN increases with age. Diabetic neuropathy is a commoncomplication of diabetes which increases with the duration of thedisease. The pain for these types of neuropathies has been described asa burning steady pain often punctuated with stabbing pains, pins andneedles pain, and toothache-like pain. The skin can be sensitive withdysesthetic sensations to even light touch and clothing. The pain can beexacerbated by activity, temperature change, and emotional upset. Thepain can be so severe as to preclude daily activities or result in sleepdisturbance or anorexia. The mechanisms involved in producing pain ofthese types are not well understood, but may involve degeneration ofmyelinated nerve fibers. It is known that in diabetic neuropathy, bothsmall and large nerve fibers deteriorate resulting in reduced thresholdsfor tolerance of thermal sensitivity, pain, and vibration. Dysfunctionof both large and small fiber functions is more severe in the lowerlimbs when pain develops. Most of the physiological measurements ofnerves that can be routinely done in patients experiencing neuropathicpain demonstrate a slowing of nerve conduction over time. To date,treatment for neuropathic pain has been less than universallysuccessful. Chronic pain is estimated to affect millions of people.

Dextromethorphan is widely used as a cough syrup, and it has been shownto be sufficiently safe in humans to allow its use as anover-the-counter medicine. It is well tolerated in oral dosage form,either alone or with quinidine, at up to 120 milligrams (mg) per day,and a beneficial effect may be observed when receiving a substantiallysmaller dose (e.g., 30 mg/day) (U.S. Pat. No. 5,206,248 to Smith).

The chemistry of dextromethorphan and its analogs is described invarious references such as Rodd, E. H., Ed., Chemistry of CarbonCompounds, Elsevier Publ., N.Y., 1960; Goodman and Gilman'sPharmacological Basis of Therapeutics; Choi, Brain Res., 1987, 403:333-336; and U.S. Pat. No. 4,806,543. Its chemical structure is asfollows:

Dextromethorphan is the common name for (+)-3-methoxy-N-methylmorphinan.It is one of a class of molecules that are dextrorotatory analogs ofmorphine-like opioids. The term “opiate” refers to drugs that arederived from opium, such as morphine and codeine. The term “opioid” isbroader. It includes opiates, as well as other drugs, natural orsynthetic, which act as analgesics and sedatives in mammals.

Most of the addictive analgesic opiates, such as morphine, codeine, andheroin, are levorotatory stereoisomers (they rotate polarized light inthe so-called left-handed direction). They have four molecular rings ina configuration known as a “morphinan” structure, which is depicted asfollows:

In this depiction, the carbon atoms are conventionally numbered asshown, and the wedge-shaped bonds coupled to carbon atoms 9 and 13indicate that those bonds rise out of the plane of the three other ringsin the morphinan structure. Many analogs of this basic structure(including morphine) are pentacyclic compounds that have an additionalring formed by a bridging atom (such as oxygen) between the number 4 and5 carbon atoms.

Many dextrorotatory analogs of morphine are much less addictive than thelevorotatory compounds. Some of these dextrorotatory analogs, includingdextromethorphan and dextrorphan, are enantiomers of the morphinanstructure. In these enantiomers, the ring that extends out from carbonatoms 9 and 13 is oriented in the opposite direction from that depictedin the above structure.

While not wishing to be limited to any particular mechanism of action,dextromethorphan is known to have at least three distinct receptoractivities which affect central nervous system (CNS) neurons. First, itacts as an antagonist at N-methyl-D-aspartate (NMDA) receptors. NMDAreceptors are one of three major types of excitatory amino acid (EAA)receptors in CNS neurons. Since activation of NMDA receptors causesneurons to release excitatory neurotransmitter molecules (primarilyglutamate, an amino acid), the blocking activity of dextromethorphan atthese receptors reduces the level of excitatory activity in neuronshaving these receptors. Dextromethorphan is believed to act at thephencyclidine (PCP) binding site, which is part of the NMDA receptorcomplex. Dextromethorphan is relatively weak in its NMDA antagonistactivity, particularly compared to drugs such as MK-801 (dizocilpine)and phencyclidine. Accordingly, when administered at approved dosages,dextromethorphan is not believed to cause the toxic side effects(discussed in U.S. Pat. No. 5,034,400 to Olney) that are caused bypowerful NMDA antagonists such as MK-801 or PCP.

Dextromethorphan also functions as an agonist at certain types ofinhibitory receptors; unlike EAA receptors, activation of inhibitoryreceptors suppresses the release of excitatory neurotransmitters byaffected cells. Initially, these inhibitory receptors were called sigmaopiate receptors. However, questions have been raised as to whether theyare actually opiate receptors, so they are now generally referred to assigma (a) receptors. Subsequent experiments showed that dextromethorphanalso binds to another class of inhibitory receptors that are closelyrelated to, but distinct from, sigma receptors. The evidence, whichindicates that non-sigma inhibitory receptors exist and are bound bydextromethorphan, is that certain molecules which bind to sigmareceptors are not able to completely block the binding ofdextromethorphan to certain types of neurons that are known to haveinhibitory receptors (Musacchio et al., Cell Mol. Neurobiol., 1988 June,8(2):149-56; Musacchio et al., J. Pharmacol. Exp. Ther., 1988 November,247(2):424-31; Craviso et al., Mol. Pharmacol., 1983 May, 23(3):629-40;Craviso et al., Mol. Pharmacol., 1983 May, 23(3):619-28; and Klein etal., Neurosci. Lett., 1989 Feb. 13, 97(1-2):175-80). These receptors aregenerally called “high-affinity dextromethorphan receptors” or simply“DM receptors” in the scientific literature. As used herein, the phrase“dextromethorphan-binding inhibitory receptors” includes both sigma andnon-sigma receptors which undergo affinity-binding reactions withdextromethorphan and which, when activated by dextromethorphan, suppressthe release of excitatory neurotransmitters by the affected cells(Largent et al., Mol. Pharmacol., 1987 December, 32(6):772-84).

Dextromethorphan also decreases the uptake of calcium ions (Ca⁺⁺) byneurons. Calcium uptake, which occurs during transmission of nerveimpulses, involves at least two different types of channels, known asN-channels and L-channels. Dextromethorphan suppressed calcium uptakefairly strongly in certain types of cultured neurons (synaptosomes)which contain N-channels; it also suppressed calcium uptake, althoughless strongly, in other cultured neurons (PC12 cells) which containL-channels (Carpenter et al., Brain Res., 1988 Jan. 26, 439(1-2):372-5).

An increasing body of evidence indicates dextromethorphan hastherapeutic potential for treating several neuronal disorders (Zhang etal., Clin. Pharmacol. Ther. 1992; 51: 647-655; Palmer G C, Curr. DrugTargets, 2001; 2: 241-271; and Liu et al., J. Pharmacol. Exp. Ther.2003; 21: 21; Kim et al., Life Sci., 2003; 72: 769-783). Pharmacologicalstudies demonstrate that DM is a noncompetitive NMDA antagonist that hasneuroprotective, anticonvulsant and antinociceptive activities in anumber of experimental models (Desmeules et al., J. Pharmacol. Exp.Ther., 1999; 288: 607-612). In addition to acting as an NMDA antagonist,both DM and its primary metabolite, dextrorphan, bind to sigma-1 sites,inhibit calcium flux channels and interact with high voltage-gatedsodium channels (Dickenson et al., Neuropharmacology, 1987; 26:1235-1238; Carpenter et al., Brain Res., 1988; 439: 372-375; Netzer etal., Eur. J. Pharmacol., 1993; 238: 209-216). Recent reports indicatethat an additional neuroprotective mechanism of DM may includeinterference with the inflammatory responses associated with someneurodegenerative disorders that include Parkinson's disease andAlzheimer's disease (Liu et al., J. Pharmacol. Exp. Ther., 2003; 21:21). The potential efficacy of DM as a neuroprotectant was explored inlimited clinical trials in patients with amyotrophic lateral sclerosis(Gredal et al., Acta Neurol. Scand. 1997; 96: 8-13; Blin et al., Clin.Neuropharmacol., 1996; 19: 189-192) Huntington's disease (Walker et al.,Clin. Neuropharmacol., 1989; 12: 322-330) and Parkinson's Disease (Chaseet al., J. Neurol., 2000; 247 Suppl 2: 1136-42). DM was also examined inpatients with various types of neuropathic pain (Mcquay et al., Pain,1994; 59: 127-133; Vinik A I, Am. J. Med., 1999; 107: 17S-26S; Weinbroumet al., Can. J. Anaesth., 2000; 47: 585-596; Sang et al.,Anesthesiology, 2002; 96: 1053-1061; Heiskanen et al., Pain, 2002; 96:261-267; Ben Abraham et al., Clin. J. Pain, 2002; 18: 282-285; Sang C N,J. Pain Symptom Manage., 2000; 19: S21-25). Although the pharmacologicalprofile of DM points to clinical efficacy, most clinical trials havebeen disappointing with equivocal efficacy for DM compared to placebotreatment.

Several investigators suggested that the limited benefit seen with DM inclinical trials is associated with rapid hepatic metabolism that limitssystemic drug concentrations. In one trial in patients with Huntington'sdisease, plasma concentrations were undetectable in some patients afterDM doses that were eight times the maximum antitussive dose (Walker etal., Clin. Neuropharmacol., 1989; 12: 322-330).

As discussed above, DM undergoes extensive hepatic O-demethylation todextrorphan that is catalyzed by CYP2D6. This is the same enzyme that isresponsible for polymorphic debrisoquine hydroxylation in humans (Schmidet al., Clin. Pharmacol. Ther., 1985; 38: 618-624). An alternate pathwayis mediated primarily by CYP3A4 and N-demethylation to form3-methoxymorphinan (Von Moltke et al., J. Pharm. Pharmacol., 1998; 50:997-1004). Both DX and 3-methoxymorphinan can be further demethylated to3-hydroxymorphinan that is then subject to glucuronidation. Themetabolic pathway that converts DM to DX is dominant in the majority ofthe population and is the principle for using DM as a probe to phenotypeindividuals as CYP2D6 extensive and poor metabolizers (Kupfer et al.,Lancet 1984; 2: 517-518; Guttendorf et al., Ther. Drug Monit., 1988; 10:490-498). Approximately 7% of the Caucasian population shows the poormetabolizer phenotype, while the incidence of poor metabolizer phenotypein Chinese and Black African populations is lower (Droll et al.,Pharmacogenetics, 1998; 8: 325-333). A study examining the ability of DMto increase pain threshold in extensive and poor metabolizers foundantinociceptive effects of DM were significant in poor metabolizers butnot in extensive metabolizers (Desmeules et al., J. Pharmacol. Exp.Ther., 1999; 288: 607-612). The results are consistent with directeffects of parent DM rather than the DX metabolite on neuromodulation.

One approach for increasing systemically available DM is to coadministerthe CYP2D6 inhibitor, quinidine, to protect DM from metabolism (Zhang etal., Clin. Pharmacol. Ther. 1992; 51: 647-655). Quinidine administrationcan convert subjects with extensive metabolizer phenotype to poormetabolizer phenotype (Inaba et al., Br. J. Clin. Pharmacol., 1986; 22:199-200). When this combination therapy was tried in amyotrophic lateralsclerosis patients it appeared to exert a palliative effect on symptomsof pseudobulbar affect (Smith et al., Neurol., 1995; 54: 604P).Combination treatment with DM and quinidine also appeared effective forpatients with chronic pain that could not be adequately controlled withother medications. This observation is consistent with a report thatshowed DM was effective in increasing pain threshold in poormetabolizers and in extensive metabolizers given quinidine, but not inextensive metabolizers (Desmeules et al., J. Pharmacol. Exp. Ther.,1999; 288: 607-612). To date, most studies have used quinidine dosesranging from 50 to 200 mg to inhibit CYP2D6 mediated drug metabolism,but no studies have identified a minimal dose of quinidine for enzymeinhibition.

The highly complex interactions between different types of neuronshaving varying populations of different receptors, and thecross-affinity of different receptor types for dextromethorphan as wellas other types of molecules which can interact with some or all of thosesame types of receptors, render it very difficult to attribute theoverall effects of dextromethorphan to binding activity at anyparticular receptor type. Nevertheless, it is believed thatdextromethorphan suppresses neuronal activity by means of at least threemolecular functions: it reduces activity at (excitatory) NMDA receptors;it inhibits neuronal activity by binding to certain types of inhibitoryreceptors; and it suppresses calcium uptake through N-channels andL-channels.

Unlike some analogs of morphine, dextromethorphan has little or noagonist or antagonist activity at various other opiate receptors,including the mu (μ) and kappa (κ) classes of opiate receptors. This ishighly desirable, since agonist or antagonist activity at those opiatereceptors can cause undesired side effects such as respiratorydepression (which interferes with breathing) and blockade of analgesia(which reduces the effectiveness of pain-killers).

Accordingly, emotional lability or pseudobulbar affect can be treated inat least some patients by means of administering a drug which functionsas an antagonist at NMDA receptors and as an agonist atdextromethorphan-binding inhibitory receptors, and wherein the drug isalso characterized by a lack of agonist or antagonist activity at mu orkappa opiate receptors, namely, dextromethorphan.

It has long been known that in most people (estimated to include about90% of the general population in the United States), dextromethorphan israpidly metabolized and eliminated by the body (Ramachander et al., J.Pharm. Sci., 1977 July, 66(7):1047-8; and Vetticaden et al., Pharm.Res., 1989 January, 6(1):13-9). This elimination is largely due to anenzyme known as the P450 2D6 (or 11D6) enzyme, which is one member of aclass of oxidative enzymes that exist in high concentrations in theliver, known as cytochrome P450 enzymes (Kronbach et al., Anal.Biochem., 1987 April, 162(1):24-32; and Dayer et al., Clin. Pharmacol.Ther., 1989 January, 45(1):34-40). In addition to metabolizingdextromethorphan, the P450 2D6 isozyme also oxidizes sparteine anddebrisoquine. It is known that the P450 2D6 enzyme can be inhibited by anumber of drugs, particularly quinidine (Brinn et al., Br. J. Clin.Pharmacol., 1986 August, 22(2):194-7; Inaba et al., Br. J. Clin.Pharmacol., 1986 August, 22(2):199-200; Brosen et al., Pharmacol.Toxicol., 1987 April, 60(4):312-4; Otton et al., Drug Metab. Dispos.,1988 January-February, 16(1):15-7; Otton et al., J. Pharmacol. Exp.Ther., 1988 October, 247(1):242-7; Funck-Brentano et al., Br. J. Clin.Pharmacol., 1989 April, 27(4):435-44; Funck-Brentano et al., J.Pharmacol. Exp. Ther., 1989 April, 249(1):134-42; Nielsen et al., Br. J.Clin. Pharmacol., 1990 March, 29(3):299-304; Broly et al., Br. J. Clin.Pharmacol., 1989 July, 28(1):29-36).

Patients who lack the normal levels of P450 2D6 activity are classifiedin the medical literature as “poor metabolizers,” and doctors aregenerally warned to be cautious about administering various drugs tosuch patients. “The diminished oxidative biotransformation of thesecompounds in the poor metabolizer (PM) population can lead to excessivedrug accumulation, increased peak drug levels, or in some cases,decreased generation of active metabolites . . . Patients with the PMphenotype are at increased risk of potentially serious untoward effects. . . ” (Guttendorf et al., Ther. Drug Monit., 1988, 10(4):490-8, page490). Accordingly, doctors are cautious about administering quinidine topatients, and rather than using drugs such as quinidine to inhibit therapid elimination of dextromethorphan, researchers working in this fieldhave administered very large quantities (such as 750 mg/day) ofdextromethorphan to their patients, even though this is known tointroduce various problems (Walker et al., Clin Neuropharmacol., 1989August, 12(4):322-30; and Albers et al., Stroke, 1991 August,22(8):1075-7).

Dextromethorphan is a weak, noncompetitive NMDA receptor antagonist thatbinds with moderate-to-high affinity to the phencyclidine site of thereceptor complex. However, DM has additional, unique pharmacologicalproperties. Binding studies suggest it is a ligand at the high affinitysigma 1 site, where it initially was proposed to act as an antagonist(Tortella et al., TiPS, 1989; 10:501-7) but more recently as an agonist(Maurice et al., Brain Res. Brain Res. Rev., 2001; 37:116-32). Sigmaligands also modulate NMDA responses (Debonnel et al., Life Sci., 1996;58:721-34). Due to its inhibitory actions on glutamate, a number ofinvestigators have treated ALS patients with DM in the hope of modifyingor arresting the disease (Askmark et al., J. Neurol. Neurosurg.Psychiatry, 1993; 56:197-200; Hollander et al., Ann. Neurol., 1994;36:920-4; and Blin et al., Clin. Neuropharmacol., 1996; 19:189-92).These trials have failed to demonstrate any benefit, possibly due to therapid and extensive metabolism of DM that occurs in approximately 90percent of the Caucasian population (referred to as extensivemetabolizers) (see Hildebrand et al., Eur. J. Clin. Pharmacol., 1989;36:315-8).

DM metabolism is primarily mediated by CYP2D6 in extensive metabolizers.This can be circumvented by co-administration of quinidine, a selectiveCYP2D6 inhibitor, at Q doses 1 to 1.5 logs below those employed for thetreatment of cardiac arrhythmias (Schadel et al., J. Clin.Psychopharmacol., 1995; 15:263-9). Blood levels of DM increase linearlywith DM dose following co-administration with Q but are undetectable inmost subjects given DM alone, even at high doses (Zhang et al., Clin.Pharmac. & Therap., 1992; 51:647-55). The observed plasma levels inthese individuals thus mimic the plasma levels observed in individualsexpressing the minority phenotype where polymorphisms in the gene resultin reduced levels of P450 2D6 (poor metabolizers). Unexpectedly, duringa study of DM and Q in ALS patients, patients reported that theiremotional lability improved during treatment. Subsequently, in a placebocontrolled crossover study (N=12) conducted to investigate this, theconcomitant administration of DM and Q administered to ALS patients wasfound to suppress emotional lability (P<0.001 compared to placebo)(Smith et al., Neurology, 1995; 45:A330).

Rapid dextromethorphan elimination may be overcome by co-administrationof quinidine along with dextromethorphan (U.S. Pat. No. 5,206,248 toSmith). The chemical structure of quinidine is as follows:

Quinidine co-administration has at least two distinct beneficialeffects. First, it greatly increases the quantity of dextromethorphancirculating in the blood. In addition, it also yields more consistentand predictable dextromethorphan concentrations. Research involvingdextromethorphan or co-administration of quinidine and dextromethorphan,and the effects of quinidine on blood plasma concentrations, aredescribed in the patent literature (U.S. Pat. No. 5,166,207, U.S. Pat.No. 5,863,927, U.S. Pat. No. 5,366,980, U.S. Pat. No. 5,206,248, andU.S. Pat. No. 5,350,756 to Smith).

The discovery that dextromethorphan can reduce the internal feelings andexternal symptoms of emotional lability or pseudobulbar affect in somepatients suffering from progressive neurological disease suggests thatdextromethorphan is also likely to be useful for helping some patientssuffering from emotional lability due to other causes, such as stroke orother ischemic (low blood flow) or hypoxic (low oxygen supply) eventswhich led to neuronal death or damage in limited regions of the brain,or head injury or trauma as might occur during an automobile,motorcycle, or bicycling accident or due to a gunshot wound.

In addition, the results obtained to date also suggest thatdextromethorphan is likely to be useful for treating some cases ofemotional lability which are due to administration of other drugs. Forexample, various steroids, such as prednisone, are widely used to treatautoimmune diseases such as lupus. However, prednisone has adverseevents on the emotional state of many patients, ranging from mild butnoticeably increased levels of moodiness and depression, up to severelyaggravated levels of emotional lability that can impair the business,family, or personal affairs of the patient.

In addition, dextromethorphan in combination with quinidine can reducethe external displays or the internal feelings that are caused by orwhich accompany various other problems such as “premenstrual syndrome”(PMS), Tourette's syndrome, and the outburst displays that occur inpeople suffering from certain types of mental illness. Although suchproblems may not be clinically regarded as emotional lability, theyinvolve manifestations that appear to be sufficiently similar toemotional lability to suggest that dextromethorphan can offer aneffective treatment for at least some patients suffering from suchproblems.

One of the significant characteristics of the treatments of preferredembodiments is that the treatments function to reduce emotional labilitywithout tranquilizing or otherwise significantly interfering withconsciousness or alertness in the patient. As used herein, “significantinterference” refers to adverse events that would be significant eitheron a clinical level (they would provoke a specific concern in a doctoror psychologist) or on a personal or social level (such as by causingdrowsiness sufficiently severe that it would impair someone's ability todrive an automobile). In contrast, the types of very minor side effectsthat can be caused by an over-the-counter drug such as adextromethorphan-containing cough syrup when used at recommended dosagesare not regarded as significant interference.

The magnitude of a prophylactic or therapeutic dose of dextromethorphanin combination with quinidine in the acute or chronic management ofemotional lability or other chronic conditions can vary with theparticular cause of the condition, the severity of the condition, andthe route of administration. The dose and/or the dose frequency can alsovary according to the age, body weight, and response of the individualpatient.

In general, it is preferred to administer the dextromethorphan andquinidine in a combined dose, or in separate doses administeredsubstantially simultaneously. The preferred weight ratio ofdextromethorphan to quinidine is about 1:1.5 or less, preferably about1:1.45, 1:1.4, 1:1.35, or 1:1.3 or less, more preferably about 1:1.25,1:1.2, 1:1.15, 1:1.1, 1:1.05, 1:1, 1:0.95, 1:0.9, 1:0.85, 1:0.8, 1:0.75,1:0.7, 1:0.65, 1:0.6, 1:0.55 or 1:0.5 or less. In certain embodiments,however, dosages wherein the weight ratio of dextromethorphan toquinidine is greater than about 1:1.5 may be preferred, for example,dosages of about 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2 or greater. Likewise,in certain embodiments, dosages wherein the ratio of dextromethorphan toquinidine is less than about 1:0.5 may be preferred, for example, about1:0.45, 1:0.4, 1:0.35, 1:0.3, 1:0.25, 1:0.2, 1:0.15, or 1:0.1 or less.When dextromethorphan and quinidine are administered at the preferredratio of 1:1.25 or less, it is generally preferred that less than 50 mgquinidine is administered at any one time, more preferably about 45, 40,or 35 mg or less, and most preferably about 30, 25, or 20 mg or less. Itmay also be preferred to administer the combined dose (or separate dosessimultaneously administered) at the preferred ratio of 1:1.25 or lesstwice daily, three times daily, four times daily, or more frequently soas to provide the patient with a preferred dosage level per day, forexample: 60 mg quinidine and 60 mg dextromethorphan per day provided intwo doses, each dose containing 30 mg quinidine and 30 mgdextromethorphan; 50 mg quinidine and 50 mg dextromethorphan per dayprovided in two doses, each dose containing 25 mg quinidine and 25 mgdextromethorphan; 40 mg quinidine and 40 mg dextromethorphan per dayprovided in two doses, each dose containing 20 mg quinidine and 20 mgdextromethorphan; 30 mg quinidine and 30 mg dextromethorphan per dayprovided in two doses, each dose containing 15 mg quinidine and 15 mgdextromethorphan; or mg quinidine and 20 mg dextromethorphan per dayprovided in two doses, each dose containing 10 mg quinidine and 10 mgdextromethorphan. The total amount of dextromethorphan and quinidine ina combined dose may be adjusted, depending upon the number of doses tobe administered per day, so as to provide a suitable daily total dosageto the patient, while maintaining the preferred ratio of 1:1.25 or less.These ratios are particularly preferred for the treatment of emotionallability and neuropathic pain.

In general, the total daily dose for dextromethorphan in combinationwith quinidine, for the conditions described herein, is about 10 mg orless up to about 200 mg or more dextromethorphan in combination withabout 1 mg or less up to about 150 mg or more quinidine; preferably fromabout 15 or 20 mg to about 65, 70, 75, 80, 85, 90, 95, 100, 110, 120,130, 140, 150, 160, 170, 180, or 190 mg dextromethorphan in combinationwith from about 2.5, 5, 7.5, 10, 15, or 20 mg to about 55, 60, 65, 70,75, 80, 85, 90, 95, 100, 110, 120, 130, or 140 mg quinidine; morepreferably from about 25, 30, 35, or 40 mg to about 55 or 60 mgdextromethorphan in combination with from about 25, 30, or 35 mg toabout 40, 45, or 50 mg quinidine. In particularly preferred embodiments,the daily dose of dextromethorphan (DM) to quinidine (O) is: 20 mg DM to20 mg Q; 20 mg DM to 30 mg Q; 20 mg DM to 40 mg Q; 20 mg DM to 50 mg Q;20 mg DM to 60 mg Q; 30 mg DM to 20 mg Q; 30 mg DM to 30 mg Q; 30 mg DMto 40 mg Q; 30 mg DM to 50 mg Q; 30 mg DM to 60 mg Q; 40 mg DM to 20 mgQ; 40 mg DM to 30 mg Q; 40 mg DM to 40 mg Q; 40 mg DM to 50 mg Q; 40 mgDM to 60 mg Q; 50 mg DM to 20 mg Q; 50 mg DM to 30 mg Q; 50 mg DM to 40mg Q; 50 mg DM to 50 mg Q; 50 mg DM to 50 mg Q; 60 mg DM to 20 mg Q; 60mg DM to 30 mg Q; 60 mg DM to 40 mg Q; 60 mg DM to 50 mg Q; or 60 mg DMto 60 mg Q. A single dose per day or divided doses (two, three, four ormore doses per day) can be administered.

Preferably, a daily dose for emotional lability is about 20 mg to about60 mg dextromethorphan in combination with about 20 mg to about 60 mgquinidine, in single or divided doses. Particularly preferred daily dosefor emotional lability is about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,or 30 mg dextromethorphan in combination with about 20, 21, 22, 23, 24,25, 26, 27, 28, 29, or 30 mg quinidine; about 30, 31, 32, 33, 34, 35,36, 37, 38, 39, or 40 mg dextromethorphan in combination with about 20,21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg quinidine; about 40, 41,42, 43, 44, 45, 46, 47, 48, 49, or 50 mg dextromethorphan in combinationwith about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg quinidine;or about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 mgdextromethorphan in combination with about 20, 21, 22, 23, 24, 25, 26,27, 28, 29, or 30 mg quinidine; in single or divided doses.

In general, the total daily dose for dextromethorphan in combinationwith quinidine, for chronic pain, such as neuropathic pain, intractablecoughing, dermatitis, tinnitus, and sexual dysfunction is preferablyabout 10 mg or less up to about 200 mg or more dextromethorphan incombination with about 1 mg or less up to about 150 mg or morequinidine. Particularly preferred total daily dosages for chronic pain,such as neuropathic pain, intractable coughing, dermatitis, tinnitus,and sexual dysfunction are about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,or 30 mg dextromethorphan in combination with about 20, 21, 22, 23, 24,25, 26, 27, 28, 29, or 30 mg quinidine; about 30, 31, 32, 33, 34, 35,36, 37, 38, 39, or 40 mg dextromethorphan in combination with about 20,21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg quinidine; about 40, 41,42, 43, 44, 45, 46, 47, 48, 49, or 50 mg dextromethorphan in combinationwith about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg quinidine;or about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 mgdextromethorphan in combination with about 20, 21, 22, 23, 24, 25, 26,27, 28, 29, or 30 mg quinidine; in single or divided doses. Similardaily doses for other indications as mentioned herein are generallypreferred.

In managing treatment, the therapy is preferably initiated at a lowerdaily dose, preferably about 20 or 30 mg dextromethorphan in combinationwith about 2.5 mg quinidine per day, and increased up to about 60 mgdextromethorphan in combination with about 75 mg quinidine, or higher,depending on the patient's global response. It is further preferred thatinfants, children, patients over 65 years, and those with impaired renalor hepatic function, initially receive low doses, and that they betitrated based on individual response(s) and blood level(s). Generally,a daily dosage of 20 to 30 mg dextromethorphan and 20 to 30 mg quinidineis well-tolerated by most patients.

It can be preferred to administer dosages outside of these preferredranges in some cases, as will be apparent to those skilled in the art.Further, it is noted that the ordinary skilled clinician or treatingphysician will know how and when to interrupt, adjust, or terminatetherapy in consideration of individual patient response.

Any suitable route of administration can be employed for providing thepatient with an effective dosage of dextromethorphan in combination withquinidine. For example, oral, rectal, transdermal, parenteral(subcutaneous, intramuscular, intravenous), intrathecal, topical,inhalable, and like forms of administration can be employed. Suitabledosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, patches, and the like. Administration ofmedicaments prepared from the compounds described herein can be by anysuitable method capable of introducing the compounds into thebloodstream. Formulations of preferred embodiments can contain a mixtureof active compounds with pharmaceutically acceptable carriers ordiluents as are known by those of skill in the art.

The present method of treatment of emotional lability can be enhanced bythe use of dextromethorphan in combination with quinidine as an adjuvantto known therapeutic agents, such as fluoxetine hydrochloride, marketedas PROZAC® by Eli Lilly and Company, and the like. Preferred adjuvantsinclude pharmaceutical compositions conventionally employed in thetreatment of the disordered as discussed herein.

The pharmaceutical compositions of the present invention comprisedextromethorphan in combination with quinidine, or pharmaceuticallyacceptable salts of dextromethorphan and/or quinidine, as the activeingredient and can also contain a pharmaceutically acceptable carrier,and optionally, other therapeutic ingredients.

The terms “pharmaceutically acceptable salts” or “a pharmaceuticallyacceptable salt thereof” refer to salts prepared from pharmaceuticallyacceptable, non-toxic acids or bases. Suitable pharmaceuticallyacceptable salts include metallic salts, e.g., salts of aluminum, zinc,alkali metal salts such as lithium, sodium, and potassium salts,alkaline earth metal salts such as calcium and magnesium salts; organicsalts, e.g., salts of lysine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), procaine, and tris; salts of free acids and bases;inorganic salts, e.g., sulfate, hydrochloride, and hydrobromide; andother salts which are currently in widespread pharmaceutical use and arelisted in sources well known to those of skill in the art, such as TheMerck Index. Any suitable constituent can be selected to make a salt ofan active drug discussed herein, provided that it is non-toxic and doesnot substantially interfere with the desired activity. In addition tosalts, pharmaceutically acceptable precursors and derivatives of thecompounds can be employed. Pharmaceutically acceptable amides, loweralkyl esters, and protected derivatives of dextromethorphan and/orquinidine can also be suitable for use in compositions and methods ofpreferred embodiments. In particularly preferred embodiments, thedextromethorphan is administered in the form of dextromethorphanhydrobromide, and the quinidine is administered in the form of quinidinesulfate. For example, a dose of 30 mg dextromethorphan hydrobromide (ofmolecular formula C₁₈H₂₅NO.HBr.H₂O) and 30 quinidine sulfate (ofmolecular formula (C₂₀H₂₄N₂O₂)₂.H₂SO₄.2H₂O) may be administered(corresponding to an effective dosage of approximately 22 mgdextromethorphan and 25 mg quinidine). Other preferred dosages include,for example, 45 mg dextromethorphan hydrobromide and 30 quinidinesulfate (corresponding to an effective dosage of approximately 33 mgdextromethorphan and approximately 25 mg quinidine); 60 mgdextromethorphan hydrobromide and 30 quinidine sulfate (corresponding toan effective dosage of approximately 44 mg dextromethorphan andapproximately 25 mg quinidine); 45 mg dextromethorphan hydrobromide and45 quinidine sulfate (corresponding to an effective dosage ofapproximately 33 mg dextromethorphan and 37.5 mg quinidine); 60 mgdextromethorphan hydrobromide and 60 quinidine sulfate (corresponding toan effective dosage of approximately 44 mg dextromethorphan and 50 mgquinidine).

The compositions can be prepared in any desired form, for example,tables, powders, capsules, suspensions, solutions, elixirs, andaerosols. Carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegratingagents, and the like can be used in oral solid preparations. Oral solidpreparations (such as powders, capsules, and tablets) are generallypreferred over oral liquid preparations. However, in certain embodimentsoral liquid preparations can be preferred over oral solid preparations.The most preferred oral solid preparations are tablets. If desired,tablets can be coated by standard aqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compounds canalso be administered by sustained release, delayed release, orcontrolled release compositions and/or delivery devices, for example,such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; and 4,008,719.

Pharmaceutical compositions suitable for oral administration can beprovided as discrete units such as capsules, cachets, tablets, andaerosol sprays, each containing predetermined amounts of the activeingredients, as powder or granules, or as a solution or a suspension inan aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or awater-in-oil liquid emulsion. Such compositions can be prepared by anyof the conventional methods of pharmacy, but the majority of the methodstypically include the step of bringing into association the activeingredients with a carrier which constitutes one or more ingredients. Ingeneral, the compositions are prepared by uniformly and intimatelyadmixing the active ingredients with liquid carriers, finely dividedsolid carriers, or both, and then, optionally, shaping the product intothe desired presentation.

For example, a tablet can be prepared by compression or molding,optionally, with one or more additional ingredients. Compressed tabletscan be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active ordispersing agent. Molded tablets can be made by molding, in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent.

Preferably, each tablet contains from about 30 mg to about 60 mg ofdextromethorphan and from about 30 mg to about 45 mg quinidine, and eachcapsule contains from about 30 mg to about 60 mg of dextromethorphan andfrom about 30 mg to about 45 mg quinidine. Most preferably, tablets orcapsules are provided in a range of dosages to permit divided dosages tobe administered. For example, tablets, cachets or capsules can beprovided that contain about 10 mg dextromethorphan and about 5, 10, or15 mg quinidine; about 20 mg dextromethorphan and about 10, 20 or 30 mgquinidine; about 30 mg dextromethorphan and about 15, 30, or 45 mgquinidine; and the like. A dosage appropriate to the patient, thecondition to be treated, and the number of doses to be administereddaily can thus be conveniently selected. While it is generally preferredto incorporate both dextromethorphan and quinidine in a single tablet orother dosage form, in certain embodiments it can be desirable to providethe dextromethorphan and quinidine in separate dosage forms.

It has been unexpectedly discovered that patients suffering fromemotional lability and other conditions as described herein can treatedwith dextromethorphan in combination with an amount of quinidinesubstantially lower than the minimum amount heretofore believed to benecessary to provide a significant therapeutic effect. As used herein, a“minimum effective therapeutic amount” is that amount which provides asatisfactory degree of inhibition of the rapid elimination ofdextromethorphan from the body, while producing no adverse effect oronly adverse events of an acceptable degree and nature. Morespecifically, a preferred effective therapeutic amount is within therange of from about 20, 25 or 30 mg to about 60 mg of dextromethorphanand less than about 50 mg of quinidine per day, preferably about 20 or30 mg to about 60 mg of dextromethorphan and about 30 mg to about 45 mgof quinidine per day, the amount being preferably administered in adivided dose based on the plasma half-life of dextromethorphan. Forexample, in a preferred embodiment dextromethorphan and quinidine areadministered in specified mg increments to achieve a targetconcentration of dextromethorphan of a specified level in μg/mL plasma,with a maximum preferred specified dosage of dextromethorphan andquinidine based on body weight. The target dose is then preferablyadministered every 12 hours. Since the level of quinidine is minimized,the side effects observed at high dosages for quinidine are minimized oreliminated, a significant benefit over compositions containingdextromethorphan in combination with higher levels of quinidine.

The combination of dextromethorphan and quinidine of preferredembodiments can also be extremely effective in formulations for thetreatment for other chronic disorders which do not respond well to othertreatments. Dextromethorphan in combination with quinidine can be usedto effectively treat severe or intractable coughing, which has notresponded adequately to non-addictive, non-steroid medications, withminimal side-effects. Intractable coughing is a consequence ofrespiratory infections, asthma, emphysema, and other conditionsaffecting the pulmonary system.

Dextromethorphan in combination with quinidine as in the preferredembodiments can also be used in pharmaceutical compositions for treatingdermatitis. As used herein, “dermatitis” or “eczema” is a skin conditioncharacterized by visible skin lesions and/or an itching or burningsensation on the skin. Dextromethorphan in combination with quinidine asin the preferred embodiments can also be used in pharmaceuticalcompositions for the treatment of chronic pain from conditions such asstroke, trauma, cancer, and pain due to neuropathies such as herpeszoster infections and diabetes. Other conditions that can be treatedusing dextromethorphan in combination with quinidine according to thepreferred embodiments can include sexual dysfunctions, such as priapismor premature ejaculation, as well as tinnitus.

Clinical Study #1

Clinical testing was conducted to determine the lowest dose of quinidinewhich inhibits the conversion of dextromethorphan to dextrorphan; and tochronicle the occurrence of side effects during administration ofdextromethorphan/quinidine.

Testing protocol specifications and a detailed time and events schedulewere prepared to assure consistent execution of the protocol throughoutthe study conduct.

A phenotyping study directed to dextromethorphan was conducted. Thestudy was an open-label single dose study. Subjects were screened toensure they met the inclusion and exclusion criteria. Subjects receiveda single oral dose of dextromethorphan hydrobromide 30 mg capsule takenwith 240 mL of tap water. A total of fifty-eight subjects were screenedand fifty subjects dosed. The study determined each subject's ability tometabolize dextromethorphan. Subjects who met the inclusion/exclusioncriteria remained in house for dosing. Each subject was administered one30 mg capsule (P.M.) of dextromethorphan. Urine was collected predosethrough 12 hours postdose and analyzed for dextromethorphan anddextrorphan. A blood sample (5 mL) was collected for analysis of plasmadextromethorphan, dextrorphan, and quinidine predose and at 2, 4 and 8hours postdose. Following a wash-out period of at least two days,forty-eight subjects determined to be extensive metabolizers ofdextromethorphan were asked to participate in the quinidine dosingstudy. Forty-six of these subjects were determined to be extensivemetabolizers of dextromethorphan. One adverse effect was reported duringthe study (a headache, classified as mild, that resolved withoutintervention).

Thereafter, a quinidine dose determination study was conducted. Thestudy was an open-label, randomized, multiple dose study. Subjectsidentified as extensive metabolizers received an evening dose on Day 1,at 12-hour intervals for the next six days, with a final morning dose onDay 8. All subjects were instructed to dose themselves at home on eightoccasions with medication dispensed to them. Subjects maintained a diaryduring the study to record adverse effects.

Subjects randomized to Treatment A received fourteen oral doses ofdextromethorphan hydrobromide 30 mg capsule taken with 240 mL of tapwater. Subjects randomized to Treatment B received fourteen oral dosesof dextromethorphan hydrobromide 30 mg/quinidine 2.5 mg capsule takenwith 240 mL of tap water. Subjects randomized to Treatment C receivedfourteen oral doses of dextromethorphan hydrobromide 30 mg/quinidine 10mg capsule taken with 240 mL of tap water. Subjects randomized toTreatment D received fourteen oral doses of dextromethorphanHydrobromide 30 mg/quinidine 25 mg capsule taken with 240 mL of tapwater. Subjects randomized to Treatment E received fourteen oral dosesof dextromethorphan hydrobromide 30 mg/quinidine 50 mg capsule takenwith 240 mL of tap water. Subjects randomized to Treatment F receivedfourteen oral doses of dextromethorphan hydrobromide 30 mg/quinidine 75mg capsule taken with 240 mL of tap water.

All subjects enrolled in the study except for one satisfied theinclusion/exclusion criteria as listed in the protocol. Medicalhistories, clinical laboratory evaluations, and performed physicalexaminations were reviewed prior to subjects being enrolled in thestudy. The subjects were instructed not to consume any grapefruitproducts while participating in the study. Over-the-counter medicationswere prohibited three days prior to dosing and during the study, andprescription medications (with the exception of oral contraceptives)were prohibited fourteen days prior to dosing and during the study.

A total of forty-six subjects, twenty-two males and twenty-four females,were enrolled in the study and forty-five subjects, twenty-two males andtwenty-three females, completed the study. The subjects were screenedwithin twenty-one days prior to study enrollment. The screeningprocedure included medical history, physical examination (height,weight, frame size, vital signs, and ECG), and clinical laboratory tests(hematology, serum chemistry, urinalysis, HIV antibody screen, serumpregnancy, and a screen for THECA).

Subjects were dosed in the clinic on the following schedule: Day 1(P.M.), Day 2 (A.M.), Day 3 (P.M.), Day 4 (A.M.) and Day 7 (P.M.). Thesubjects reported to the clinic on Day 8 for the A.M. dosing andremained in house for 8 hours postdose. Subjects self medicated at homeon Day 2 (P.M.), Day 3 (A.M.), Day 4 (P.M.), Day 5 (A.M. and P.M.), Day6 (A.M. and P.M.), and Day 7 (A.M.). Subjects were dosed twice dailyexcept they received only a PM dose on Day 1 and an AM dose on Day 8.

A clinical laboratory evaluation (hematology, chemistries, urinalysis),vital signs, ECG, and a brief physical examination were performed at thecompletion of the study. Subjects were instructed to inform the studyphysician and/or safety nurses of any adverse events that occurredduring the study.

Blood samples (5 mL) were collected on Day 8 prior to dosing and at 2, 4and 8 hours postdose for analysis of dextromethorphan, dextrorphan, andquinidine. A total of eight blood samples (40 mL) were drawn during thestudy (including the dextromethorphan screen) for drug analysis. Plasmasamples were separated by centrifugation and then frozen at −20° C. andkept frozen until assayed. Urine was collected predose through twelvehours post doses 1, 5, and 13. Urine samples were pooled for the entirecollection interval. At the end of the interval, the total volume wasrecorded and two aliquots were frozen at −20° C. until assayed fordextromethorphan and dextrorphan.

A total of forty-six subjects were dosed and forty-five subjectscompleted the study. One subject was discontinued/withdrawn from thestudy as not tolerating adverse events experienced. The mean age of thesubjects was 51 years (range of 20 through 86), the mean height of thesubjects was 67.6 inches (range of 61.5 through 74.5), and the meanweight of the subjects was 162.9 pounds (range 101.0 through 229.0).

A total of eight subjects were enrolled in Treatment Groups B, D, and E.Seven subjects were enrolled in Treatment Groups A and C.

A total of 150 adverse events were experienced by thirty-four subjects(74%). Other than one serious adverse effect, all adverse events wereclassified as mild (96%) or moderate (4%). The most frequently reportedadverse events included headache, loose stool, lightheadedness,dizziness, and nausea. The relationship to study drug was classified aspossibly, probably, or almost certainly for 120 of the 150 adverseevents (80%). There were no clear differences between dose groups in thetype or frequency of adverse events observed. No clinically significanttrends regarding vital signs, physical examinations or clinicallaboratory tests were observed.

Clinical Study #2

The objectives of this study were to determine pharmacokineticparameters of dextromethorphan upon single-dose and multiple-doses of acapsule formulation containing 30 mg dextromethorphan hydrobromide and25 mg quinidine sulfate capsules, to determine the differences in thesepharmacokinetic parameters for extensive metabolizers and poormetabolizers, and to chronicle the occurrence of side effects duringadministration of the formulation. This study had an open-label, single,and multiple dose design.

Ten subjects were enrolled in the study. A total of nine subjectscompleted the study. Ten subjects were included in safety analyses, andnine were included in pharmacokinetic analyses. All subjects enrolled inthis study were judged by the investigator to be normal, healthyvolunteers.

The test formulation was 30 mg dextromethorphan hydrobromide and 25 mgquinidine sulfate capsules. All subjects received one 30 mgdextromethorphan hydrobromide and 25 mg quinidine sulfate capsule takenorally with 240 mL of water every 12 hours for a total of 15 doses.

The noncompartmental pharmacokinetic parameters Cmax, Tmax, and AUC(0-12) were calculated from the plasma concentration-time data fordextromethorphan, dextrorphan, and quinidine on Days 1, 4, and 8. Inaddition, the parameters Kel and T ½el were calculated for dextrorphan(Day 8), and quinidine (Days 1, 4, and 8).

The amount of dextromethorphan and dextrorphan excreted in the urine wascalculated from the 12-hour urine collections on Day 1 (postdose 1), Day8 (postdose 15), and Days 9-14. The molar metabolic ratio(dextromethorphan:dextrorphan) was calculated for each urine-collectionday.

Subjects were evaluated by physical examination, vital signs,electrocardiogram (ECG), clinical laboratory (hematology, serumchemistry, and urinalysis), and adverse event assessment.

Descriptive statistics for each parameter, including mean, median,standard deviation, coefficient of variation, N, minimum, and maximumwere calculated for all of the subjects by Day. In addition, descriptivestatistics were presented by the subgroups: extensive metabolizer (EM)and poor metabolizer (PM).

A normal theory, general linear model (GLM) was applied to thelog-transformed parameters Cmax and AUC (0-12), and untransformed Tmax(dextromethorphan and dextrorphan), and to untransformed parametersCmax, AUC (0-12), and Tmax (quinidine). The ANOVA model included thefactors group (EM or PM), subject within group, day, and the interactionterm day by group. The group effect was tested using the subject withingroup mean square, and all other main effects were tested using theresidual error (error mean square). In addition, tests of the hypothesesDay 1=Day 4, Day 1=Day 8, and Day 4=Day 8 were performed.

Safety and tolerability were assessed via data listings and calculationof summary statistics as follows: hematology, serum chemistry, andurinalysis test results from predose and postdose were listed inby-subject data listings. Descriptive statistics were reported by timepoint of collection, and changes from predose to postdose weresummarized and statistically tested using the paired t-test (H_(o):change=0). Shift tables describing out-of-range shifts from predose topostdose were created. Out-of-normal range and clinically significantlaboratory values were listed by subject.

Descriptive statistics (mean, standard deviation, minimum, maximum, andsample size) were reported by time point (screen and Day 8 postdose) forvital sign measurements: systolic and diastolic blood pressure, pulserate, respiration and temperature. Summary statistics were presented bymetabolizer type. Differences between screening and postdosemeasurements were presented and statistically tested using a pairedt-test (H_(o): difference=0). Individual vital signs results were listedin by-subject data listings. Changes in physical examination resultsthat occurred from predose to postdose were also identified.

Twelve-lead ECGs were recorded prior to dosing. Descriptive statistics(mean, standard deviation, minimum, maximum, and sample size) werereported by time point (predose and Day 8 postdose) for ECGmeasurements: QRS, PR, QTc, and heart rate. Summary statistics werepresented by metabolizer type. Differences between predose and Day 8postdose measurements were presented and statistically testing using apaired t-test (H_(o): difference=0). ECG results were listed inby-subject data listings.

Adverse events were classified using the 5^(th) Edition of the COSTARTdictionary. Summary tables include number of subjects reporting theadverse event and as percent of number of subjects dosed by metabolizertype. Summary tables were also presented by adverse event frequency,severity, and relationship to study medication. Adverse events werelisted by subject, including verbatim term, severity, frequency, andrelationship to treatment in data listings.

Mean pharmacokinetic parameters for dextromethorphan, dextrorphan, andquinidine are summarized in Table 1 for extensive metabolizers ofdextromethorphan (EMs), poor metabolizers of dextromethorphan (PMs), andall subjects.

TABLE 1 Pharmaco- Metabolizer Type kinetics EM PM AllSubjects CompoundParameter Day Mean N S.D. Mean N S.D. Mean N S.D. Dextrome- Cmax 1 15.897 8.22 22.30 2 0.14 17.31 9 7.66 thorphan (ng/mL) 4 76.69 7 15.28 105.702 9.48 83.13 9 18.71 8 95.50 7 19.92 136.20 2 3.25 104.54 9 24.92 Tmax(hr) 1 6.85 7 2.78 8.00 2 0.00 7.11 9 2.46 4 5.42 7 1.90 6.00 2 2.825.55 9 1.94 8 5.99 7 2.58 4.99 2 1.41 5.77 9 2.33 AUC (0-12) 1 133.27 759.86 198.33 2 6.97 147.73 9 59.30 (ng*hr./ml) 4 811.68 7 151.7 1146.4 284.43 886.07 9 199.8 8 1049.0 7 243.3 1533.5 2 80.97 1156.7 9 301.4 T1/2el (hr) 8 13.13 6 3.41 41.96 2 4.47 20.33 8 13.76 Dextrorphan Cmax 1124.86 7 53.26 10.80 2 3.39 99.51 9 68.25 (ng/ml) 4 79.33 7 18.63 37.052 0.21 69.93 9 24.65 8 123.51 7 17.07 51.45 2 4.17 107.50 9 35.08 Tmax(hr) 1 4.00 7 0.00 3.00 2 1.42 3.78 9 0.67 4 2.21 7 1.40 2.00 2 0.002.17 9 1.22 8 41.18 7 11.57 2.99 2 1.41 32.70 9 19.61 AUC (0-12) 1933.83 7 324.8 90.95 2 19.08 748.52 9 466.2 (ng*hr/mL) 4 849.22 7 181.9365.27 2 30.37 741.68 9 265.4 8 1000.5 7 147.2 530.40 2 82.39 896.04 9245.1 Quinidine Cmax 1 0.09 7 0.02 0.08 2 0.01 0.09 9 0.02 (μg/ml) 40.15 7 0.03 0.14 2 0.01 0.15 9 0.03 8 0.16 7 0.04 0.16 2 0.02 0.16 90.03 Tmax (hr) 1 1.71 7 0.27 1.50 2 0.00 1.67 9 0.25 4 1.65 7 0.37 1.522 0.00 1.62 9 0.33 8 1.99 7 0.01 1.49 2 0.00 1.88 9 0.22 AUC (0-12) 10.48 7 0.18 0.51 2 0.13 0.49 9 0.17 (μg*hr/mL) 4 1.20 7 0.21 0.97 2 0.051.15 9 0.21 8 1.31 7 0.19 1.07 2 0.02 1.26 9 0.19 T 1/2el (hr) 1 8.11 72.95 8.25 2 2.65 8.14 9 2.72 4 6.86 7 1.11 6.51 2 0.70 6.78 9 1.01 87.66 7 1.09 6.66 2 0.41 7.44 9 1.05

Mean urinary metabolic ratios (dextromethorphan:dextrorphan) aresummarized in Table for extensive metabolizers of dextromethorphan(EMs), poor metabolizers of dextromethorphan (PMs), and all subjects.

TABLE 2 Metabolizer Type EM PM All Subjects Day Mean N S.D. Mean N S.D.Mean N S.D.  1 0.268 7 0.227 1.790 2 0.493 0.608 9 0.721  8 0.804 70.366 1.859 2 0.507 1.039 9 0.591  9 0.445 6 0.170 1.398 2 0.597 0.683 80.516 10 0.198 7 0.152 2.538 2 1.593 0.718 9 1.183 11 0.145 7 0.1252.200 2 1.136 0.601 9 0.997 12 0.091 7 0.086 3.333 2 0.090 0.812 9 1.43213 0.037 7 0.064 2.250 2 0.554 0.529 9 0.997 14 0.027 5 0.061 2.061 20.115 0.608 7 0.995

No serious adverse events occurred during this study. Drug relatedadverse events included asthenia, diarrhea, anorexia, nausea, vomiting,anxiety, depersonalization, insomnia, and somnolence. The majority ofthe adverse events were mild in severity and all were resolved withouttreatment. Prolonged QT intervals and decreased ventricular rates wereobserved for the extensive metabolizer group following dosing. Noclinically significant trends regarding vital signs, physicalexaminations, or routine clinical laboratory tests were observed.

Over the course of this study, low dose quinidine inhibited themetabolism of dextromethorphan, resulting in increased systemicavailability. This effect was most pronounced in extensive metabolizers.The mean urinary metabolic ratio (dextromethorphan:dextrorphan)increased at least 29-fold in extensive metabolizers by Day 8. Theplasma dextrorphan AUC (0-12) increased approximately 8-fold between Day1 and Day 8, whereas the mean plasma dextrorphan AUC (0-12) remained thesame between Day 1 and Day 8.

The effect of quinidine on dextromethorphan metabolism in poormetabolizers was unclear. The urinary metabolic ratios did not appear tochange with quinidine treatment. The excretion of both dextromethorphanand dextrorphan increased. However, dextrorphan excretion increasedproportionally to dextromethorphan. This suggests that quinidine did notinhibit dextromethorphan metabolism to dextrorphan in poor metabolizers.However, there was 6.1-fold increase in dextromethorphan AUC (0-12) fromDay 1 to Day 8, compared to a 4.8-fold increase in dextrorphan AUC(0-12), which is consistent with a small decrease in metabolicclearance.

Quinidine pharmacokinetics were similar between extensive metabolizersand poor metabolizers. Mean quinidine elimination half-life values (6.78to 8.14 hours) were similar to previously reported values.

Dextromethorphan hydrobromide and quinidine sulfate capsulesadministered as a single-dose or multiple-doses product appeared to bewell tolerated in this healthy population.

Clinical Study #3

The objectives of this study were to determine the lowest dose ofquinidine sulfate that effectively inhibits the conversion of 45 mg ofdextromethorphan to dextrorphan and the lowest dose of quinidine thateffectively inhibits the conversion of 60 mg of dextromethorphan todextrorphan, and to chronicle the occurrence of side effects duringadministration of dextromethorphan in combination with quinidine.

This dose interaction study was a Phase 1, open-label, parallel group,multiple-dose, single-center, safety, and pharmacokinetic study. A totalof sixty-four subjects were planned, and sixty-five subjects wereenrolled in the study. A total of forty-seven subjects completed thestudy and were included in pharmacokinetic analyses. All subjects wereincluded in safety analyses. Males and females between 18 and 60 yearsof age, identified as extensive metabolizers of dextromethorphan, wereenrolled. All subjects were judged to be healthy volunteers. Enrolledsubjects met inclusion and exclusion criteria.

The test formulation was dextromethorphan hydrobromide and quinidinesulfate capsules, administered orally with water. Subjects receivingTreatment A received an oral dose of one dextromethorphan hydrobromideof 60 mg/0 mg quinidine sulfate capsule taken twice daily with 240 mL ofwater on Days 1 through 8. Subjects receiving Treatment B received anoral dose of one dextromethorphan hydrobromide of 60 mg/30 mg quinidinesulfate capsule taken twice daily with 240 mL of water on Days 1 through8. Subjects receiving Treatment C received an oral dose of onedextromethorphan hydrobromide of 60 mg/45 mg quinidine sulfate capsuletaken twice daily with 240 mL of water on Days 1 through 8. Subjectsreceiving Treatment D received an oral dose of one dextromethorphanhydrobromide of 60 mg/60 mg quinidine sulfate capsule taken twice dailywith 240 mL of water on Days 1 through 8. Subjects receiving Treatment Ereceived an oral dose of one dextromethorphan hydrobromide of 45 mg/0 mgquinidine sulfate capsule taken twice daily with 240 mL of water on Days1 through 8. Subjects receiving Treatment F received an oral dose of onedextromethorphan hydrobromide of 45 mg/30 mg quinidine sulfate capsuletaken twice daily with 240 mL of water on Days 1 through 8. Subjectsreceiving Treatment G received an oral dose of one dextromethorphanhydrobromide of 45 mg/45 mg quinidine sulfate capsule taken twice dailywith 240 mL of water on Days 1 through 8. Subjects receiving Treatment Hreceived an oral dose of one dextromethorphan hydrobromide of 45 mg/60mg quinidine sulfate capsule taken twice daily with 240 mL of water onDays 1 through 8. For Treatments B, C, D, F, G, and H, subjects receiveda single dose of dextromethorphan hydrobromide (either 60 mg forTreatments B, C, and D or 45 mg for Treatments F, G, and H) withoutquinidine for the first dose and then 14 does of the designated capsule,i.e., all subjects received one dose of either Treatment A or E as abaseline.

The first dose of Treatments A and E was considered as reference.Dextromethorphan hydrobromide 30 mg capsules were used for phenotyping.Subjects received a single oral dose of one dextromethorphanhydrobromide 30 mg capsule taken with 240 mL of water.

The plasma pharmacokinetic parameters, Cmax, Tmax, AUC (0-5), and AUC(0-12) were calculated using noncompartmental analysis. Pharmacokineticparameters were summarized and descriptive statistics for all groupswere calculated. Changes in these parameters from baseline werecalculated and summarized. Urine metabolic ratios(dextromethorphan/dextrorphan) were calculated. Descriptive statisticsfor all groups were calculated, and changes in metabolic ratio frombaseline were calculated and summarized.

Adverse events assessments, monitoring of hematology, blood chemistry,and urine values, measurements of vital signs and electrocardiogram(ECG) as well as the performance of physical examinations were evaluatedfor safety.

The effect of quinidine on the pharmacokinetics of dextromethorphan wasassessed by measuring serial plasma dextromethorphan and dextrorphanconcentrations on Days 1 and 8, quinidine concentrations on Day 8, andthe amount of dextromethorphan and dextrorphan excreted in the urine for12-hour urine collections on Day, 1, Day 3, and Day 7, following amultiple dose administration of dextromethorphan and quinidine. Thenoncompartmental pharmacokinetic parameters Cmax, Tmax, AUC (0-5), andAUC (0-12) were calculated from the plasma concentration-time data fordextromethorphan and dextrorphan on Days 1 and 8, quinidine on Day 8.The amount of dextromethorphan and dextrorphan excreted in the urine wascalculated from the 12-hour urine collections on Day 1, Day 3, and Day7. The molar metabolic ratio (dextromethorphan:dextrorphan) wascalculated for each urine-collection day. To assess the effect ofquinidine on dextromethorphan, analysis of variance was performed usingSAS PROC Mixed on the parameter AUC of dextromethorphan from the 4dextromethorphan and quinidine treatments, respectively, for 60 mg and45 mg dextromethorphan doses. Least square means of doses, thedifferences (pairwise comparisons) between doses, plus the P-values forthe significance of the differences were presented. To assess the effectof dextromethorphan on quinidine, analysis of variance was performedusing SAS PROC Mixed on the parameter AUC of quinidine. Least squaremeans of doses, the differences (pairwise comparisons) between doses,plus the P-values for the significance of the differences werepresented.

Safety and tolerability were assessed through calculation of summarystatistics and were displayed in data listings of individual subjects.Adverse events were coded using the MedDRA Adverse Event Dictionary(Version 3.0, 2000). The frequency, type, severity, and relationship tostudy drug of treatment-emergent adverse events were displayed andcompared across treatments.

For laboratory tests, the study screening and poststudy measurements,along with the change between these time points, were summarized bydescriptive statistics (median, mean, standard deviation, minimum,maximum, and sample size) for serum chemistry and hematology tests.Shift tables from screening to poststudy for serum chemistry,hematology, and urinalysis laboratory tests were constructed.Out-of-range clinical laboratory results and their associated recheckvalues were listed.

Descriptive statistics (median, mean, standard deviation, minimum,maximum, and sample size) were calculated for vital signs and 12-leadelectrocardiogram (ECG) measurements for baseline and postdose, alongwith the change between these time points. The ECG shift table frombaseline to postdose was also presented.

The arithmetic means of pharmacokinetic parameters of plasmadextromethorphan, dextrorphan, and quinidine following Treatments A, B,C, D, E, F, G, and H, and results of statistical comparisons betweentreatment groups are presented in the following tables. Table 3 providesa summary of the plasma DM pharmacokinetic parameters following a 60 mgdose of dextromethorphan.

TABLE 3 Pharmacokinetic Treatment A Treatment B Treatment C Treatment DParameters Day* Mean S.D. Mean S.D. Mean S.D. Mean S.D. Cmax (ng/mL) 13.7 3.70 2.1 2.82 3.5 3.19 4.8 4.74 8 7.7 7.01 191.8 45.48 204.8 22.93231.9 96.36 C 4.0 4.75 189.7 43.90 201.3 22.19 227.1 97.52 Tmax (hr) 12.6 0.96 2.5 0.57 2.4 0.56 3.5 1.05 8 2.1 0.38 3.5 1.73 3.7 1.17 5.21.94 C −0.5 1.12 1.0 1.42 1.3 1.51 1.7 1.97 AUC (0-t) 1 23.0 23.64 12.116.04 20.7 17.39 32.0 34.66 (ng*hr/mL) 8 52.3 46.72 1963.0 608.50 2121.0278.50 2252.0 689.30 C 29.3 34.57 1951.0 600.30 2100.0 275.90 2220.0697.70 AUC (0-12) 1 23.2 23.50 12.3 15.93 20.7 17.39 32.2 34.45(ng*hr/mL) 8 52.3 46.72 1963.0 608.50 2121.0 278.50 2252.0 689.30 C 29.234.79 1951.0 600.10 2100.0 275.90 2220.0 697.80 1n (Cmax) 1 0.9 1.07 0.11.21 0.9 1.05 1.2 0.88 8 1.6 1.03 5.2 0.24 5.3 0.11 5.4 0.40 C 2.3 1.03219.5 132.00 108.8 92.40 85.0 54.87 In (AUC (0-12) 1 2.7 1.07 2.0 1.082.8 0.95 3.1 0.98 8 3.6 1.02 7.5 0.33 7.7 0.13 7.7 0.32 C 2.6 1.22 324.9185.30 170.9 130.30 141.0 114.80 * = Code C corresponds to the changefrom the baseline, calculated as follows: for the untransformedparameters, it is the difference between Day 8 and Baseline values, forthe In-transformed parameters, it is the ratio of Day 8 over Baselinevalues.

Table 4 provides a summary of statistical comparisons of plasmadextromethorphan AUC (0-12) relating to the effect of quinidine doses ona 60 mg dose of dextromethorphan.

TABLE 4 Treatment Comparison Geometric Means Ratio of GEOMEANS P A vs. D35.11 2159.23 0.02 0.0001 B vs. D 1888.72 2159.23 0.87 0.7601 C vs. D2108.96 2159.23 0.98 0.9608

Table 5 provides a summary of statistical comparisons of plasmadextromethorphan AUC (0-t) relating to the effect of quinidine doses ona 60 mg dose of dextromethorphan.

TABLE 5 Treatment Comparison Geometric Means Ratio of GEOMEANS P A vs. D35.11 2159.23 0.02 0.0001 B vs. D 1888.72 2159.23 0.87 0.7601 C vs. D2108.96 2159.23 0.98 0.9608

Table 6 provides a summary of plasma dextromethorphan pharmacokineticparameters following a 45 mg dose of dextromethorphan.

TABLE 6 Pharmacokinetic Treatment E Treatment F Treatment G Treatment HParameters Day* Mean S.D. Mean S.D. Mean S.D. Mean S.D. Cmax (ng/mL) 12.3 1.60 9.6 13.91 3.6 5.04 1.7 1.08 8 4.2 3.01 141.5 74.68 138.9 25.97136.1 50.59 C 1.9 2.03 131.9 62.92 135.3 23.87 134.4 50.80 Tmax (hr) 13.5 0.93 2.9 0.37 3.4 1.40 3.0 1.0 8 3.4 0.50 4.3 1.70 3.3 1.80 3.6 2.07C −0.1 1.16 1.4 1.51 −0.1 1.21 0.6 2.20 AUC (0-t) 1 14.9 11.39 77.5120.80 25.4 36.89 10.2 7.08 (ng*hr/mL) 8 31.3 23.85 1438.0 842.60 1403.0283.10 1464.0 588.60 C 16.3 17.0 1360.0 736.20 1378.0 259.50 1453.0589.30 AUC (0-12) 1 15.0 11.36 77.5 120.80 25.5 36.79 10.3 6.98(ng*hr/mL) 8 31.5 23.64 1488.0 842.60 1403.0 283.10 1464.0 588.50 C 16.516.82 1360.0 736.20 1378.0 259.60 1453.0 589.50 1n (Cmax) 1 0.5 0.95 1.21.56 0.5 1.33 0.4 0.55 8 1.1 1.09 4.8 0.52 4.9 0.19 4.8 0.45 C 1.9 0.9362.6 54.58 138.3 107.10 100.3 59.37 In (AUC (0-t) 1 2.2 1.45 3.2 1.642.3 1.45 2.1 0.65 8 3.0 1.23 7.1 0.54 7.2 0.19 7.2 0.50 C 2.6 1.60 89.678.74 241.2 206.30 188.5 112.20 In (AUC (0-12) 1 2.3 1.34 3.2 1.64 2.41.39 2.2 0.62 8 3.0 1.17 7.1 0.54 7.2 0.19 7.2 0.50 C 2.5 1.38 89.678.74 218.9 177.50 185.4 113.80 * = Code C corresponds to the changefrom the baseline, calculated as follows: for the untransformedparameters, it is the difference between Day 8 and Baseline values, forthe In-transformed parameters, it is the ratio of Day 8 over Baselinevalues.

Table 7 provides a summary of statistical comparisons of plasmadextromethorphan AUC (0-12) relating to the effect of quinidine doses ona 60 mg dose of dextromethorphan.

TABLE 7 Treatment Comparison Geometric Means Ratio of GEOMEANS P E vs. H20.89 1342.73 0.02 0.0001 F vs. H 1266.94 1342.73 0.94 0.8945 G vs. H1380.84 1342.73 1.03 0.9490

Table 8 provides a summary of statistical comparisons of plasmadextromethorphan AUC (0-t) relating to the effect of quinidine doses ona 60 mg dose of dextromethorphan.

TABLE 8 Treatment Comparison Geometric Means Ratio of GEOMEANS P E vs. H20.18 1342.73 0.02 0.0001 F vs. H 1266.94 1342.73 0.94 0.8980 G vs. H1380.84 1342.73 1.03 0.9490

Table 9 provides a summary of plasma dextromethorphan pharmacokineticparameters following a 60 mg dose of dextromethorphan.

TABLE 9 Pharmacokinetic Treatment A Treatment B Treatment C Treatment DParameters Day* Mean S.D. Mean S.D. Mean S.D. Mean S.D. Cmax (ng/mL) 1663.6 111.69 858.1 75.95 885 .4 33.23 655.5 145.57 8 709.6 88.82 176.741.40 90.1 24.55 110.8 27.68 C 46.0 142.71 −681.4 75.24 −795.3 57.72−544.8 126.32 Tmax (hr) 1 2.2 0.37 2.0 0.01 2.0 0.03 2.0 0.01 8 2.1 0.381.6 1.60 5.3 5.77 4.3 4.13 C −0.0 0.58 −0.4 1.59 3.3 5.78 2.3 4.13 AUC(0-t) 1 3240.0 494.10 3953.0 516.80 3669.0 468.10 3237.0 515.10(ng*hr/mL) 8 3608.0 386.80 1830.0 443.10 958.0 248.80 1157.0 281.30 C367.9 581.60 −2123.0 322.70 −2711.0 467.40 −2080.0 369.40 AUC (0-12) 13240.0 494.10 3953.0 516.80 3669.0 468.10 3237.0 515.10 (ng*hr/mL) 83608.0 386.80 1830.0 443.10 958.0 248.80 1157.0 281.30 C 367.9 581.60−2123.0 322.70 −2711.0 467.40 −2080.0 369.40 1n (Cmax) 1 6.5 0.16 6.80.09 6.8 0.04 6.5 0.23 8 6.6 0.12 5.2 0.24 4.5 0.27 4.7 0.27 C 1.1 0.220.2 0.05 0.1 0.03 0.2 0.04 In (AUC (0-t) 1 8.1 0.15 8.3 0.13 8.2 0.138.1 0.16 8 8.2 0.11 7.5 0.26 6.8 0.25 7.0 0.27 C 1.1 0.19 0.5 0.08 0.30.07 0.4 0.06 In (AUC (0-12) 1 8.1 0.15 8.3 0.13 8.2 0.13 8.1 0.16 8 8.20.11 7.5 0.26 6.8 0.25 7.0 0.27 C 1.1 0.19 0.5 0.08 0.3 0.07 0.4 0.06 *= Code C corresponds to the Change from the baseline, calculated asfollows: for the untransformed parameters, it is the difference betweenDay 8 and Baseline values, for the In-transformed parameters, it is theratio of Day 8 over Baseline values.

Table 10 provides a summary of statistical comparisons of plasmadextromethorphan AUC (0-12) as relates to the effect of quinidine doseson 60 mg of Dextromethorphan.

TABLE 10 Treatment Comparison Geometric Means Ratio of GEOMEANS P A vs.D 3589.57 1125.35 3.19 0.0001 B vs. D 1786.16 1125.35 1.59 0.0046 C vs.D 937.28 1125.35 0.83 0.2521

Table 11 provides a summary of statistical comparisons of plasmadextromethorphan AUC (0-t) as relates to the effect of quinidine doseson 60 mg of Dextromethorphan.

TABLE 11 Treatment Ratio of Comparison Geometric Means GEOMEANS P A vs.D 3589.57 1125.35 3.19 0.0001 B vs. D 1786.16 1125.35 1.59 0.0046 C vs.D 937.28 1125.35 0.83 0.2521

Table 12 provides a summary of plasma dextromethorphan pharmacokineticparameters following a 45 mg dose of dextromethorphan.

TABLE 12 Pharmacokinetic Treatment E Treatment F Treatment G Treatment HParameters Day* Mean S.D. Mean S.D. Mean S.D. Mean S.D. Cmax (ng/mL) 1587.4 172.23 446.6 216.16 554.0 209.23 607.3 125.85 8 599.2 199.89 89.125.97 86.8 23.11 77.7 15.81 C 11.9 94.36 −357.5 215.39 −467.2 188.06−529.6 126.09 Tmax (hr) 1 2.0 0.00 2.0 0.01 2.2 .038 2.0 0.01 8 2.0 0.012.3 1.38 1.0 1.12 1.3 1.20 C 0.0 0.01 0.3 1.38 −1.2 1.25 0.7 1.20 AUC(0-t) 1 2618.0 603.10 2260.0 751.50 2462.0 737.10 2860.0 580.40(ng*hr/mL) 8 2898.0 900.50 920.7 275.90 874.1 283.80 782.6 129.9 C 280.7430.70 −1340.0 751.40 −1588.0 537.30 −2078.0 535.00 AUC (0-12) 1 2618.0603.10 2260.0 751.50 2481.0 732.00 2860.0 580.40 (ng*hr/mL) 8 2898.0900.50 920.7 275.90 874.1 238.80 782.6 129.90 C 280.7 430.70 −1340.0751.40 −1607.0 536.50 −2078.0 535.00 1n (Cmax) 1 6.3 0.30 6.0 0.62 6.30.37 6.4 0.20 8 6.3 0.35 4.5 0.29 4.4 0.27 4.3 0.20 C 1.0 0.19 0.3 0.240.2 0.03 0.1 0.04 In (AUC (0-t) 1 7.8 0.22 7.7 0.39 7.8 0.27 7.9 0.21 87.9 0.31 6.8 0.31 6.7 0.28 6.7 0.17 C 1.1 0.17 0.5 0.24 0.4 0.05 0.30.06 In (AUC (0-12) 1 7.8 0.22 7.7 0.39 7.8 0.27 7.9 0.21 8 7.9 0.31 6.80.31 6.7 0.28 6.7 0.17 C 1.1 0.17 0.5 0.24 0.4 0.05 0.3 0.06 * = Code Ccorresponds to the Change from the baseline, calculated as follows: forthe untransformed parameters, it is the difference between Day 8 andBaseline values, for the In-transformed parameters, it is the ratio ofDay 8 over Baseline values.

Table 13 provides a summary of statistical comparisons of plasmadextromethorphan AUC (0-12) as relates to the effect of quinidine doseson a 45 mg dose of dextromethorphan.

TABLE 13 Treatment Ratio of Comparison Geometric Means GEOMEANS P E vs.H 2777.40 773.75 3.59 0.0001 F vs. H 884.33 773.75 1.14 0.4276 G vs. H846.26 773.75 1.09 0.5933

Table 14 provides a summary of statistical comparisons of plasmadextromethorphan AUC (0-t) as relates to the effect of quinidine doseson a 45 mg dose of dextromethorphan.

TABLE 14 Treatment Ratio of Comparison Geometric Means GEOMEANS P E vs.H 277.40 773.75 3.59 0.0001 F vs. H 884.33 773.75 1.14 0.4276 G vs. H846.26 773.75 1.09 0.5933

Table 15 provides a summary of plasma dextromethorphan pharmacokineticparameters following a 60 mg dose of dextromethorphan.

TABLE 15 Pharmacokinetic Treatment A Treatment B Treatment C Treatment DParameters Day* Mean S.D. Mean S.D. Mean S.D. Mean S.D. Cmax (mcg/mL) 80.0 0.00 0.1 0.05 0.3 0.02 0.3 0.15 Tmax (mcr) 8 . . 2.3 1.26 1.3 0.581.8 0.40 AUC (0-Tt ) (mcg-hr/mL) 8 0.0 0.00 0.9 0.40 1.9 0.10 2.4 1.29AUC (0-12) (mcg*hr/mL) 8 0.0 0.00 1.0 0.34 1.9 0.10 2.5 1.22 1n (Cmax) 8. . −2.0 0.33 −1.3 0.07 −1.1 0.43 1n[AUC (0-t)] 8 . . −0.2 0.40 0.6 0.050.8 0.58 1n[AUC (0-12)] 8 . . −0.1 0.33 0.6 0.05 0.8 0.51 * = ForQuinidine only Day 8 data were analyzed

Table 16 provides a summary of plasma dextromethorphan pharmacokineticparameters following a 45 mg dose of dextromethorphan.

TABLE 16 Pharmacokinetic Treatment E Treatment F Treatment G Treatment HParameters Day* Mean S.D. Mean S.D. Mean S.D. Mean S.D. Cmax (mcg/mL) 80.0 0.00 0.2 0.11 0.3 0.13 0.3 0.06 Tmax (mcr) 8 . . 1.6 0.79 1.2 0.571.8 1.3 AUC(0-Tt) (mcg- 8 0.0 0.00 1.0 0.77 2.0 0.91 2.3 0.71 hr/mL)AUC(0-12) 8 0.0 0.00 1.1 0.74 2.0 0.88 2.3 0.64 (mcg*hr/mL) 1n(Cmax) 8 .. −1.8 0.58 −1.3 0.44 −1.1 0.19 1n[AUC(0-t)] 8 . . −0.2 0.66 0.6 0.480.8 0.33 1n[AUC(0-12)] 8 . . −0.1 0.61 0.6 0.44 0.8 0.28 *= ForQuinidine, only Day 8 data were analyzed

Table 17 provides a summary of statistical comparisons of plasmaquinidine AUC (0-12) as relates to different dextromethorphan/quinidinedose combinations.

TABLE 17 Treatment Ratio of Comparison Geometric Means GEOMEANS P F vs.B 0.94 0.94 1.00 0.9925 G vs. C 1.88 1.89 1.00 0.9930 H vs. D 2.24 2.231.01 0.9765

Table 18 provides a summary of statistical comparisons of plasmaquinidine AUC (0-t) as relates to different dextromethorphan/quinidinedose combinations.

TABLE 18 Treatment Ratio of Comparison Geometric Means GEOMEANS P F vs.B 0.84 0.84 1.00 0.9987 G vs. C 1.84 1.89 0.97 0.9421 H vs. D 2.18 2.121.03 0.9294

A summary of the metabolic ratios for urinary pharmacokinetic parametersfollowing a 60 mg dose of dextromethorphan are provided in Table 19.

TABLE 19 Treatment A Treatment B Treatment C Treatment D PharmacokineticArithmetic Arithmetic Arithmetic Arithmetic Period Parameters Mean S.D.Mean S.D. Mean S.D. Mean S.D.   0-12 hr Ae 0.0013 0.0023 0.0010 0.00150.0027 0.0048 0.0041 0.0070 CumAe 0.0013 0.0023 0.0010 0.0015 0.00270.0048 0.0041 0.0070  12-24 hr Ae 0.0058 0.0055 0.0865 0.0496 0.27480.2228 0.2934 0.2046 CumAe 0.0031 0.0039 0.0253 0.0116 0.0641 0.05040.0632 0.0362  60-72 hr Ae 0.0133 0.0122 0.8139 0.3464 1.3598 0.74542.0366 0.9219 CumAe 0.0058 0.0061 0.1248 0.0545 0.2374 0.1904 0.29660.1670 156-168 hr Ae 0.0179 0.0163 0.6513 0.4119 1.1785 0.1517 1.30230.7430 CumAe 0.0085 0.0092 0.2005 0.1129 0.3493 0.1676 0.4374 0.17670-12 hr collecting period corresponds to Baseline, when onlyDextromethorphan (no Quinidine) was administered at the specific dose.Ae = Amount excreted (mcg) CumAe = Cumulative Amount Excreted (mcg)

A summary of statistical comparisons of urinary metabolic ratio for Ae(156-168 Hr) as relates to the effect of quinidine doses on a 60 mg doseof dextromethorphan are provided Table 20.

TABLE 20 Treatment Ratio of Comparison Geometric Means GEOMEANS P A vs.D 0.01 1.12 0.01 0.0001 B vs. D 0.54 1.12 0.49 0.1947 C vs. D 1.17 1.121.05 0.9347

A summary of statistical comparisons of urinary metabolic ratio forCumAe (156-168 Hr) as relates to the effect of quinidine doses on a 60mg dose of dextromethorphan are provided Table 21.

TABLE 21 Treatment Ratio of Comparison Geometric Means GEOMEANS P A vs.D 0.01 0.41 0.02 0.0001 B vs. D 0.18 0.41 0.45 0.0822 C vs. D 0.32 0.410.80 0.6485

A summary of the metabolic ratios for urinary pharmacokinetic parametersfollowing a 45 mg dose of dextromethorphan are provided in Table 22.

TABLE 22 Treatment A Treatment B Treatment C Treatment D PharmacokineticArithmetic Arithmetic Arithmetic Arithmetic Period Parameters Mean S.D.Mean S.D. Mean S.D. Mean S.D.   0-12 hr Ae 0.0022 0.0043 0.0454 0.07680.0130 0.0271 0.0017 0.0025 CumAe 0.0022 0.0043 0.0454 0.0768 0.01300.0271 0.0017 0.0025  12-24 hr Ae 0.0044 0.0043 0.2338 0.1996 0.26470.1224 0.3252 0.1955 CumAe 0.0032 0.0043 0.1078 0.1130 0.0798 0.03930.0774 0.0554  60-72 hr Ae 0.0089 0.0096 1.2159 0.4110 1.2594 0.50560.8073 0.4256 CumAe 0.0052 0.0061 0.3673 0.1438 0.2837 0.1087 0.18890.0621 156-168 hr Ae 0.0087 0.0097 0.9387 0.2688 1.6276 0.7287 0.87700.4967 CumAe 0.0059 0.0054 0.4826 0.1201 0.4912 0.2480 0.3468 0.14770-12 hr collecting period corresponds to Baseline, when onlyDextromethorphan (no Quinidine) was administered at the specific dose.Ae = Amount excreted (mcg) CumAe = Cumulative Amount Excreted (mcg)

A summary of statistical comparisons of urinary metabolic ratio for Ae(156-168 Hr) as relates to the effect of quinidine doses on a 45 mg doseof dextromethorphan are provided Table 23.

TABLE 23 Ratio Treatment Comparison Geometric Means of GEOMEANS P E vs.H 0.01 0.75 0.01 0.0001 F vs. H 0.90 0.75 1.20 0.5713 G vs. H 1.46 0.751.95 0.0469

A summary of statistical comparisons of urinary metabolic ratio forCumAe (156-168 Hr) as relates to the effect of quinidine doses on a 45mg dose of dextromethorphan are provided Table 24.

TABLE 24 Ratio Treatment Comparison Geometric Means of GEOMEANS P E vs.H 0.01 0.32 0.02 0.0001 F vs. H 0.47 0.32 1.48 0.2201 G vs. H 0.43 0.321.36 0.3345

The data suggest that co-administration of dextromethorphan andquinidine sulfate is safe and moderately well tolerated up to thehighest dose level (60 mg dextromethorphan/60 mg quinidine).

There were a total of 279 treatment-emergent adverse events experiencedby forty-eight of the sixty-five subjects dosed (74%) during the trial.There were 206 adverse events reported by twenty-seven of the thirty-twosubjects dosed (84%) following the 60 mg dextromethorphan treatments andseventy-three adverse events reported by twenty-one of the thirty-threesubjects dosed (64%) following the 45 mg dextromethorphan treatments.Twelve subjects following the 60 mg dextromethorphan treatments and fivesubjects following the 45 mg dextromethorphan treatments werediscontinued from the trial due to adverse events.

Dizziness, nausea, and headache were the most common adverse eventsfollowing both dextromethorphan groups, and fewer adverse events werereported following the 45 mg dextromethorphan treatments. All of theadverse events were mild or moderate in severity and no serious adverseevents occurred. No clinically significant differences were observedbetween the treatment groups regarding clinical laboratory results,vital signs, physical examination, or ECG results.

Over the course of this study, quinidine inhibited the metabolism ofdextromethorphan dosed at 45 and 60 mg resulting in increased systemicavailability of dextromethorphan. The 60 mg quinidine dose resulted inthe largest dextromethorphan AUC at both the 45 and 60 mgdextromethorphan doses, compared to the 30 and 45 mg quinidine doses.The statistical comparisons, however, showed there were not onlystatistically significant differences in the quinidine inhibition ofdextromethorphan metabolism among the different quinidine doses. Basedon dextromethorphan AUC statistical comparisons, the lowest effectivedose of quinidine that inhibits the metabolism of 45 and 60 mgdextromethorphan is 30 mg. Thus, a 30 mg quinidine dose is recommendedfor dextromethorphan inhibition.

The occurrence of side effects during the co-administration ofdextromethorphan and quinidine sulfate indicated the treatments weremoderately well tolerated up to the highest dose level (60 mgdextromethorphan/60 mg quinidine).

Clinical Study #4

The objectives of this study were to compare and evaluate the efficacy,safety, and tolerance of a combination of 30DM/30Q taken twice dailyrelative to 30 mg DM and 30 mg Q taken individually in a population ofALS subjects with pseudobulbar affect.

This was a multicenter, randomized, double-blind, controlled,parallel-group study. All study drugs were self-administered orallyevery twelve hours for twenty-eight days. The study included a screeningvisit and three other clinic visits on Days 1, 15, and 29. Day 29 wasthe last day the subject was on study and could occur anywhere betweenthe morning of Day 26 and the morning of Day 32.

Subjects with clinically diagnosed pseudobulbar affect were screened forgeneral health within four weeks before entry into the study. Alleligible subjects had attained a score of 13 or above on the Center forNeurologic Study-Lability Scale (CNS-LS) at the clinic visit on Day 1.

Subjects were randomized to one of three treatment groups to receive30DM/30Q, or 30 mg DM, or 30 mg Q. They received a diary in which theyrecorded the date and time each dose was taken, the number oflaughing/crying episodes experienced, and any adverse events that hadoccurred since the last visit. Diary cards were collected on Day 15 andat the time of study completion.

Subjects completed the CNS-LS questionnaire and visual analog scalesassessing quality of life (QOL) and quality of relationships (QOR) everytwo weeks (Days 1, 15, and 29) during the treatment period. A clinicalpsychologist, or other approved clinician, administered the HamiltonRating Scale for Depression (HRSD) at the Screening Visit and on Day 29.Safety was evaluated on Day 15 and Day 29 by examining adverse events,results of physical examinations, vital signs, clinical laboratoryvalues, and resting electrocardiograms (ECGs). In addition to bloodsamples taken to provide clinical laboratory data, blood was also takenfor pharmacokinetic analysis and CYP2D6 genotyping. Each subjectcompleted a diary in which the number of episodes experienced,medications taken, and any adverse events were recorded daily.

DM and Q were chosen as control groups because they are the componentsof the drug investigated in this study (30DM/30Q).

Subjects included in the study were 18 to 80 years of age, inclusive.The subjects had a confirmed diagnosis of ALS or probable ALS accordingto the World Federation of Neurology (WFN) criteria, and a clinicalhistory of pseudobulbar affect. Every effort was made by the to continuea subject in the study; however, if the subject decided to withdraw, allefforts were made to complete all assessments listed on Day 29 in Table25. An explanation of why the subject withdrew from the study wasobtained. Subjects who withdrew from the study could not re-enter it,and no subject who had been randomized was replaced.

The study drugs were randomized in blocks of four. Each block containedtwo assignments to the 30DM/30Q, one to DM and one to Q in random order.Specifically, each block was constructed by selecting one of the fourpossibilities to be received first. From the three remaining treatments,one was selected to be received next, and so forth. Subject numbers wereallocated to study sites in one block of four assignments at a time.

There were three treatments administered in the study: 30DM/30Q, or 30mg DM, or 30 mg Q. Study medications were provided as hard, gelatincapsules. The contents of the capsules is listed in Table 25. Allmedication used in the study was prepared according to current GoodManufacturing Practice (cGMP).

TABLE 25 Amount (mg) Ingredient DM/Q DM Q Dextromethorphan hydrobromide31.50 31.50 0.00 monohydrate USP Quinidine sulfate dihydrate USP 31.400.00 31.40 Croscarmellose sodium NF 7.80 7.80 7.80 Microcrystallinecellulose NF 94.00 109.70 109.75 Colloidal silicone dioxide NF 0.65 0.650.65 Lactose monohydrate NF 94.00 109.70 109.75 Magnesium stearate NF0.65 0.65 0.65

Subjects took one capsule twice a day (every 12 hours) for twenty-eightdays. The first dose was taken in the evening of Day 1, and the finaldose was taken in the morning on Day 29. The investigators were suppliedwith capsules of 30DM/30Q, DM, and Q in identical blister-packs, and allcapsules were identical in appearance and weight.

Subjects could not take any disallowed medications during the study orfor one week before the start of dosing on Day 1. These medicationsincluded amantadine, amitriptyline, any anti-depressant medicationincluding St. John's Wort, any monoamine oxidase inhibitor, aspirin (forpain or fever acetaminophen was recommended), captopril, cimetidine,desipramine, dextromethorphan (over-the-counter cough medicines),digoxin, diltiazem, erythromycin, fluoxetine, imipramine, itraconazole,ketoconazole, nortriptyline, paroxetine, quinidine, quinine, andverapamil. At each visit, subjects were queried as to whether or notthey had taken any medications, and if they had, the medication wasrecorded on the Case Report Form.

Subjects were instructed to bring unused study medication to the visiton Day 15 visit and to return all unused study medication to the clinicat the end of study participation. Percent of doses taken was calculatedas the total number of doses taken divided by the total number of dosesplanned, and the result was multiplied by 100. Subjects were consideredto be compliant if they had taken 80% of their prescribed doses.

The primary efficacy variable was the CNS-LS score. All efficacyvariables involving a change were determined by the baseline score beingsubtracted from the mean of the non-missing scores on Days 15 and 29.The secondary efficacy variables were laughing/crying episodes, QOLscores, and QOR scores. All efficacy variables involving a change weredetermined by subtracting the baseline score from the mean of the scoreson Days 15 and 29.

The CNS-LS questionnaire used to assess primary efficacy is a seven-itemself-report measure that provides a score for total pseudobulbar affect;it required approximately five minutes for the subject to complete. Therange of possible scores was 7 to 35. The cut-off score of 13 wasselected because it has been reported in the literature to provide thehighest incremental validity, accurately predicting the neurologists'diagnoses for 82% of participants with a sensitivity of 0.84 and aspecificity of 0.81. This questionnaire is the only instrument for themeasurement of pseudobulbar affect validated for use with ALS subjects.

Secondary efficacy was assessed by using two, 10-cm visual analog scales(VAS). One scale asked subjects to rate how much uncontrollablelaughter, tearfulness, or anger had affected the overall quality oftheir life during the past week, and one scale asked subjects to ratehow much uncontrollable laughter, tearfulness, or anger had affected thequality of their relationships with others during the past week. Eachscale required less than one minute to complete. The subjects recordedepisodes of pathological laughing and crying in a diary daily.

Safety was assessed by the following measurements: adverse events;clinical laboratory values; vital signs; physical examinations; andresting ECGs. An adverse event was defined any untoward medicaloccurrence or unintended change from the subject's baseline(pre-treatment) condition, including intercurrent illness, that occursduring the course of a clinical trial after treatment has started,whether considered related to treatment or not. An adverse event was anyunfavorable and unintended sign (including an abnormal laboratoryfinding, for example), symptom, or disease temporally associated withthe use of a medicinal product, whether or not considered related to themedicinal product. Changes associated with normal growth and developmentnot varying in frequency or magnitude from that ordinarily anticipatedclinically are not adverse events (for example, onset of menstruationoccurring at a physiologically appropriate time). Clinical adverseevents were described by diagnosis and not by symptoms when possible(for example, cold or seasonal allergies, instead of “runny nose”).

The severity of adverse events was graded on a 3-point scale andreported in detail as indicated on the Case Report Form: mild—easilytolerated, causing minimal discomfort, and not interfering with normaleveryday activities; moderate—sufficiently discomforting to interferewith normal everyday activities; and severe—incapacitating and/orpreventing normal everyday activities. The relationship of studymedication to each adverse event was determined by the investigator byusing the following definitions: not related—the event was clearlyrelated to other factors, such as the subject's clinical state,therapeutic interventions, or concomitant medications administered tothe subject; unlikely—the event was most likely produced by otherfactors, such as the subject's clinical state, therapeuticinterventions, or concomitant medications administered to the subject,and did not follow a known response pattern to the study drug;possible—the event followed a reasonable temporal sequence from the timeof drug administration, and/or followed a known response pattern to thestudy drug, but could have been produced by other factors, such as thesubject's clinical state, therapeutic interventions, or concomitantmedications administered to the subject; probable—the event followed areasonable temporal sequence from the time of drug administration,followed a known response pattern to the trial drug, and could not bereasonably explained by other factors, such as the subject's clinicalstate, therapeutic interventions, or concomitant medicationsadministered to the subject; highly probable—the event followed areasonable temporal sequence from the time of drug administration, andfollowed a known response pattern to the trial drug, and could not bereasonably explained by other factors, such as the subject's clinicalstate, therapeutic interventions, or concomitant medicationsadministered to the subject, and either occurs immediately followingstudy drug administration or improves on stopping the drug or reappearson repeat exposure.

A serious adverse event was any adverse event occurring at any dose thatresulted in any of the following outcomes: death; life-threateningexperience (one that places the subject at immediate risk of death fromthe adverse event as it occurred, for example, it does not include anadverse event that, had it occurred in a more severe form, might havecaused death); persistent or significant disability/incapacity(disability is a substantial disruption of a person's ability to conductnormal life functions); in-patient hospitalization or prolongation ofhospitalization; and congenital anomaly/birth defect.

Subjects were instructed to promptly report any adverse event. Theserious adverse event was assessed for the following details:seriousness of event, start date, stop date, intensity, frequency,relationship to test drug, action taken regarding test drug, treatmentrequired, and outcome to date. These details were recorded on the CaseReport Form. Such preliminary reports were followed by detaileddescriptions that included copies of hospital case reports, autopsyreports, and other documents when requested and applicable.

Blood and urine were collected at the screening visit and Day 29 forclinical chemistry, hematology, urinalysis, and pregnancy testing. Inthe event of an abnormal laboratory test value, the test was repeatedwithin one week, and the subject was followed up until the valuereturned to the normal range and/or until an adequate explanation of theabnormality was found.

Values were obtained for systolic and diastolic blood pressure, heartrate, and respiration rate on the screening visit and all other studyvisits. All values outside the pre-defined ranges were flagged in thesubject data listings. Electrocardiography (twelve lead) was used toobtain ventricular rate (VR), QT, Q-T, intervals, pulse rate (PR), andQRS duration. A blood sample (10 mL whole blood) was taken from eachsubject at the Screening Visit for CYP2D6 genotyping to determine whichsubjects were poor metabolizers of DM and which were extensivemetabolizers. Blood samples were taken on Day 29 for the determinationof concentrations of DM, DX, and Q in plasma. The relationship betweenthe concentration of drug in plasma and changes in CNS-LS scores wasdetermined, and the effect of the CYP2D6 genotype on this relationshipwas evaluated.

Sample sizes of forty-eight subjects in the 30DM/30Q group andtwenty-four subjects in each of the DM and Q groups were sufficient todetect a difference in CNS-LS score of 5.5 between the DM/Q group andeach of the other groups. These calculations were based on standarddeviations of 7, 5, and 3 in the DM/Q, DM, and Q groups, respectively.The power is approximately 85% based on a 2-sided, 5% test, assumingbaseline/Day 15 and baseline/Day 29 correlations are both 0.3, and theDay 15/Day 29 correlation is 0.7. The assumptions on which sample sizeswere based were drawn from a small, fourteen subject crossover study, inwhich DM/Q subjects had a mean change from baseline of −6.6 points withstandard deviation of 7.5; and placebo-treated subjects had a meanchange of +0.83 with a standard deviation of 3.2.

A total of 140 subjects were randomized to treatment; seventy were inthe 30DM/30Q group, thirty-three were in the DM group, and thirty-sevenwere in the Q group. The sample size calculations required that there beonly forty-eight subjects in the 30DM/30Q group and twenty-four subjectsin each of the other treatment groups. Therefore, under the assumptionsmade in the sample size calculations, the number of subjects in eachgroup was adequate to detect the defined difference in treatment effect.The percent of subjects with compliance≧80% was 73.5 in the 30DM/30Qgroup, 87.9 in the DM group, and 86.5 in the Q group.

Three data sets were analyzed in this study; the safety data setconsisting of data for 140 subjects, the intent-to-treat data setconsisting of data for 129 subjects, and the efficacy-evaluable data setconsisting of data for 101 subjects. The definitions of these threepopulations are as follows: safety population—all randomized subjects;intent-to-treat population—all randomized subjects who are not “poormetabolizers” of cytochrome P450 2D6; and efficacy evaluablepopulation—all subjects in the ITT population who were protocoladherent. Subjects were considered adherent if they completed the visiton Day 29, completed all study procedures, and took 80% of theirscheduled doses.

The demographic characteristics of the ITT population are provided inTable 26; the history of ALS is in Table 27, and the scores at baselinefor depression, pseudobulbar affect, QOL, and QOR are in Table 28.

TABLE 26 P-values^(a) 30DM/ 30DM/30Q DM Q 30Q 30DM/30Q Category (N = 65)(N = 30) (N = 34) vs DM vs Q Age (years) n 65 30 34 Mean 54.82 53.7755.32 0.7788 0.9976 Std Dev 12.79 11.25 9.47 Median 55 54 58 Min/Max38/82 33/75 35/72 Gender, n (%) Female 23 (35.4) 14 (46.7) 12 (35.3)0.1549 0.8105 Male 42 (64.6) 16 (53.3) 22 (64.7) Race, n (%) Asian 0(0)   1 (3.3) 0 (0)   0.2100 0.5522 Black 2 (3.1) 0 (0)   0 (0)  Caucasian 58 (89.2) 25 (83.3) 31 (91.2) Hispanic 5 (7.7)  3 (10.0) 3(8.8) Other  0 (0.00) 1 (3.3)  0 (0.00) ^(a)P-values to compare meansfor continuous variables are computed by using ANOVA with an adjustmentfor treatment and center to obtain overall F-tests. P-values forcategorical values were computed by using Cochran-Mantel-Haenszelchi-square with an adjustment for center.

TABLE 27 P-values^(a) 30DM/ 30DM/30Q DM Q 30Q 30DM/30Q Category (N = 65)(N = 30) (N = 34) vs DM vs Q ALS Type, n (%) Bulbar 29 (44.6) 14 (46.7)21 (61.8) 0.8341 0.0793 Limb 36 (55.4) 16 (53.3) 13 (38.2) WeeklyEpisode of Laughing/Crying n 65 30 34 Mean 22.18 38.93 19.35 0.08970.7043 Std Dev 31.62 66.28 19.04 Median 11 17 13 Min/Max 2/210 1/3502/70 ^(a)P-values to compare means for continuous variables are computedby using ANOVA with an adjustment for treatment and center to obtainoverall F-tests. P-values for categorical values were computed by usingCochran-Mantel-Haenszel chi-square with an adjustment for center.

TABLE 28 P-values^(b) 30DM/ 30DM/ 30DM/ Baseline 30Q DM Q 30Q 30QCharacteristics^(a) (N = 65) (N = 30) (N = 34) vs DM vs Q HRSD N 65 3034 Mean 5.37 4.27 5.79 0.1404 0.7066 Std Dev 4.33 3.05 4.20 Median 4.03.5 5.0 Min/Max 0/16 0/14 0/15 CNS-LS n 65 30 34 Mean 20.06 21.40 22.260.3202 0.0705 Std Dev 5.46 6.17 5.22 Median 19.0 20.0 21.0 Min/Max11/33  13/35  13/33  VAS-QOL n 65 30 34 Mean 35.05 47.57 46.56 0.02090.0261 Std Dev 26.70 27.24 26.93 Median 33.0 48.5 42.0 Min/Max 0/96 5/95 2/100 VAS-QOR n 65 30 34 Mean 31.77 41.07 42.18 0.1435 0.0646 Std Dev28.50 28.16 29.93 Median 28.0 41.5 34.5 Min/Max 0/99 0/95  0/100^(a)HRSD = Hamilton Rating Scale for Depression; CNS-LS = Center forNeurologic Study Lability Scale; VAS = Visual Analog Scale; QOL =Quality of Life; QOR = Quality of Relationships. Baseline measurementsfor HRSD were done at screening. Baseline measurements for CNS-LS,VAS-QOL, and VAS-QOR were done on Day 1. ^(b)P-values to compare meanswere computed by using ANOVA with an adjustment for treatment and centerto obtain overall F-tests.

There were no statistically significant differences between the 30DM/30Qgroup and the DM and Q groups for any demographic variable. The onlystatistically significant difference in the baseline characteristics wasin the QOL scores. Subjects in the 30DM/30Q group rated their QOL betterat baseline than did the subjects in either of the other two treatmentgroups. Similar demographic results were obtained in theefficacy-evaluable population, and the trend in the baselinecharacteristics was in the same direction as that in the ITT population.The population of interest in the primary and secondary analyses ofefficacy was the ITT population. Therefore, all results shown in thetext are those obtained from this population.

The primary efficacy analysis was the change from baseline in CNS-LSscores, adjusted for center and baseline CNS-LS score. The descriptivestatistics for the ITT Population are in Table 29.

TABLE 29 Change in 30DM/30Q DM Q Score^(a) (N = 65) (N = 30) (N = 34) n61 30 34 Mean −7.39 −5.12 −4.91 Std Dev 5.37 5.56 5.56 Median −6.50−4.50 −4.25 Min/Max −24.00/0.0 −25.00/2.0 −21.00/2.0 ^(a)Change inCNS-LS scores was defined as the mean of scores on Day 15 and Day 29minus the baseline (Day 1) score.

The distributions of CNS-LS scores at baseline, Day 15, and Day 29 foreach of the three treatment groups are provided in FIG. 1. Thesedistributions have not been adjusted for baseline scores or for studysite. As shown in FIG. 1, the distributions of CNS-LS scores aresymmetrical and contain only one outlier. These distributions supportthe use of ANCOVA for the analysis of the CNS-LS scores. Asprospectively specified in the protocol, the differences in meanimprovement in CNS-LS scores, adjusted for center and baseline CNS-LSscores, were analyzed by using linear regression according to the ANCOVAmethod of Frison and Pocock. The results of this analysis are in Table30. The results of additional analyses without any adjustments or withan adjustment for baseline CNS-LS score alone are also in this table.

TABLE 30 30DM/30Q Statistics 30DM/30Q vs DM vs Q Unadjusted differencein mean score −2.27 −2.47 Std Err 1.22 1.17 p-value 0.0652 0.0366Difference in mean score adjusted for −2.97 −3.65 baseline CNS-LS scoreStd Err 1.03 1.00 p-value 0.0046 0.0004 Difference in mean scoreadjusted for −3.29 −3.71 baseline CNS-LS score and center ^(b) Std Err1.00 0.97 p-value 0.0013 0.0002 ^(a)Change in CNS-LS scores was definedas the mean of the scores on Day 15 and Day 29 minus the baseline(Day 1) score. ^(b)Analysis in italics was pre-specified in theStatistical Analysis Plan.

The mean score in the group treated with 30DM/30Q was statisticallysignificantly different from the mean scores of the group treated withDM and from the mean scores of the group treated with Q. Therefore,subjects treated with 30DM/30Q showed a significant improvement inpseudobulbar affect.

The results for the analysis pre-specified in the protocol are showngraphically in FIG. 2. Adjusted mean reductions in CNS-LS scores for thethree treatment groups from the primary efficacy analysis of the ITTpopulation. Reductions in CNS-LS scores below the horizontal lines arestatistically significantly different from 30DM/30Q at the significancelevels indicated.

The primary efficacy analysis was also done for the efficacy-evaluableand the safety populations. These results are in Table 31. The resultsin these populations also showed that 30DM/30Q significantly improvedpseudobulbar affect.

TABLE 31 P-values vs 30DM/30Q Statistics^(b) DM Q DM Q ITT Population (n= 125) Difference vs 30DM/ −3.29 −3.71 0.0013 0.0002 30Q Std Error 1.000.97 Efficacy Evaluable Population (n = 101) Difference vs 30DM/ −3.78−5.00 0.0009 <0.0001 30Q Std Error 1.10 1.10 Safety Population (n = 136)Difference vs 30DM/ −3.09 −4.23 0.0016 <0.0001 30Q Std Error 0.96 0.93^(a)The ITT and EFF populations excluded poor metabolizers.^(b)Differences are mean differences in the CNS-LS reduction,controlling for baseline CNS-LS and study site, using the analysispre-specified in the Statistical Analysis Plan.

The results in these populations also showed that 30DM/30Q significantlyimproved pseudobulbar affect.

The primary efficacy data were also analyzed by using linear regressionaccording to the ANCOVA method of Frison and Pocock with an adjustmentfor center, baseline CNS-LS scores, and treatment-by-center interaction.Because of small sample sizes at some centers, this interaction couldnot be estimated.

An analysis of secondary efficacy data was conducted. Weekly episodecounts were analyzed by using the Poisson regression model as specifiedin the statistical analysis plan, and the results are in Table 32.

TABLE 32 Episode^(a) 30DM/30Q DM Q Statistic (N = 65) (N = 30) (N = 34)Laughing n 62 30 34 Wtd. Mean^(b) 4.70 35.29 6.79 Wtd. Std Dev 49.66709.97 53.93 Median 0.66 2.50 2.23 Min/Max 0.00/116.67 0.00/726.550.00/45.00 Crying n 62 30 34 Wtd. Mean^(b) 2.04 4.30 5.64 Wtd. Std Dev33.99 32.86 28.14 Median 0.44 0.70 4.00 Min/Max 0.00/66.00  0.00/21.00 0.00/19.83 Laughing/Crying n 62 30 34 Wtd. Mean^(b) 6.74 39.58 12.45Wtd. Std Dev 69.23 707.62 69.91 Median 2.00 8.97 6.19 Min/Max0.00/116.67 0.00/726.55 0.00/49.00 ^(a)The number of episodes werecollected continuously by each subject in a diary. The diaries werereviewed at the visits on Days 15 and 29. ^(b)The mean across allsubjects was the weighted mean of each subject's mean (total number ofepisodes divided by the total number of days). The weight is the numberof days in the study for each subject.

This analysis of episode rates, pre-specified in the protocol, showedthat total episodes were 6.4 times greater (calculated by using theepisode rates from the Poisson regression model with an adjustment forcenter) in the DM group than in the 30DM/30Q group and were 1.9 timesgreater in the Q group than in the 30DM/30Q group. A single outlier inthe DM group was a subject who reported 10 times more episodes than anyother subject in the study—an average of over 100 episodes per day. Whenthis outlier was omitted, the ratios were 2.3 and 1.8 for the DM and Qgroups, respectively. In each case, the calculated p-values were<0.0001. Separate assessments for crying and laughing were also highlystatistically significant. This subject's extreme episodes counts wereprimarily laughing episodes; as a result, the estimated effects oncrying were changed little by omitting this subject.

For the assessments for episode counts described above, there isevidence of substantial overdispersion in the data, signifying that thedata did not meet the assumptions of the model. A number of additionalanalyses were carried out to assess the sensitivity of the conclusionsto model specification; these analyses are discussed below.

When the data were analyzed by using the quadratic-variance (meandispersion) negative binomial model (one model for overdispersion), theresults indicated that 30DM/30Q crying rates were twice as large asthose for DM (p=0.06) and 4.5 times as large as those for Q (p<0.001).The corresponding factors for laughing were 2.6 (p=0.10) and 0.9(p=0.84) and for total are 2.6 (p=0.013) and 1.5 (p=0.29). However,there is a continued lack of fit of the data in this model also.

The data were also analyzed by using the proportional-variance (constantdispersion) negative binomial model (another model that takesoverdispersion into account). The results, indicated by an analysis ofresiduals, showed a better fit to this overdispersed data. The estimatedratios from this model for crying were 2.0 (p=0.007) and 3.3 (p<0.001)relative to DM and Q, respectively. For laughing, the ratios were 1.4and 1.5, with p-values of 0.21 and 0.13 for DM and Q, respectively.(With the outlier subject omitted, the laughing ratios were 1.5 (p=0.14)and 1.6 (p=0.05). Total counts had ratios of 1.7 and 1.8, with p-values0.02 and 0.006 relative to DM and Q, respectively.

When center was omitted from the model as a sensitivity analysis, themagnitude of response was similar to the analyses with center. Thep-values increased somewhat, as expected. The normal probability plotsof residuals from these models, however, indicate that adjustment forcenter substantially improved the normality of the residuals.

Additional studies to determine the sensitivity of the results to modelassumptions were also carried out. These analyses explored nonparametricapproaches, as well as an assessment designed to examine “steady-state”differences between groups.

The assessment of statistical significance of the relative effects of30DM/30Q, DM, and Q is dependent on the model assumptions used. However,statistical estimates of the relative effects in all models consistentlyfavored 30DM/30Q over DM and Q, even when statistical significance wasnot reached. In the model for which the assumptions best describe theobserved data, these differences were statistically significant.

To help quantify and understand how changes in the primary efficacyvariable, CNS-LS score, affect episode count, the effect of a 1-pointdifference in CNS-LS score on the episode rate during the previous twoweeks was estimated. For each 1-point increase in CNS-LS score, theaverage episode rate increased 12%. Thus, a 3.5-point decrease in CNS-LSscore would correspond to a 50% decrease in episode rate. This was truefor both laughing and crying episodes. Summary statistics of QOL and QORscores are in provided in Table 33.

TABLE 33 30DM/30Q DM Q Change in Score^(a) (N = 65) (N = 30) (N = 34)All Days QOL n 51 27 32 Mean −23.34 −17.41 −18.97 Std Dev 24.38 27.6128.30 Median −19.0 −11.0 −14.3 Min/Max −84.0/29   −90.5/27   −98.0/19  QOR n 51 27 32 Mean −22.36 −9.98 −14.14 Std Dev 27.32 22.09 27.54 Median−12.00 −4.50 −10.50 Min/Max −90.0/24.0 −71.0/23.5 −74.5/42.0 Day 15 QOLn 52 28 33 Mean −20.54 −17.14 −15.94 Std Dev 23.05 29.06 28.51 Median−18 −13 −6 Min/Max −84/28 −90/55 −96/22 QOR n 52 28 33 Mean −20.77−11.75 −12.15 Std Dev 26.11 24.88 29.05 Median −10 −7 −2 Min/Max −89/25−71/34 −84/41 Day 29 QOL n 60 29 33 Mean −24.13 −19.31 −21.15 Std Dev25.77 29.29 30.97 Median −17 −7 −14 Min/Max −90/30 −91/27 −100/23 QOR n59 29 33 Mean −22.42 −10.38 −15.67 Std Dev 27.92 23.62 27.85 Median−13.0 −3.0 −13.0 Min/Max −91/34 −71/26 −77/43 ^(a)The change in VASscores for all days was defined as the mean of the scores on Days 15 and29 minus the score on Day 1; the change in score for Day 15 was definedas the score on Day 15 minus the score on Day 1; and the score on Day 29was defined as the score on Day 29 minus the score on Day 1.

The differences in the mean changes in QOL and QOR scores between30DM/30Q and DM and Q, adjusted for baseline and study site, are inTable 34. The group treated with 30DM/30Q showed a statisticallysignificant improvement in these scores when compared with the grouptreated with DM and compared with the group treated with Q. Theseresults were similar for all time periods.

TABLE 34 Variable Statistics^(a) 30DM/30Q vs DM 30DM/30Q vs Q All DaysQOL Difference −15.00 −14.67 Std Err 4.58 4.44 p-value^(b) 0.0015 0.0013QOR Difference −18.35 −16.08 Std Err 4.27 4.16 p-value <0.0001 0.0002Day 15 QOL Difference −11.11 −12.60 Std Err 4.03 4.63 p-value 0.02350.0077 QOR Difference −15.04 −15.25 Std Err 4.49 4.32 p-value 0.00120.0006 Day 29 QOL Difference −16.33 −13.57 Std Err 4.78 4.62 p-value0.0009 0.0041 QOR Difference −19.14 −14.77 Std Err 4.33 4.24 p-value<0.0001 0.0007 ^(a)Change in VAS “all-day” scores was defined as themean of the scores on Day 15 and Day 29 minus the baseline (Day 1)score. Change in the scores on Day 15 and Day 29 was defined as thescore on that day minus the baseline score. Differences in changedscores were adjusted for baseline levels and center effects.^(b)P-values were computed by using linear regression according to theANOVA method of Frison and Pocock with an adjustment for center andbaseline QOL and QOR scores.

To account for multiple comparisons, all the secondary efficacyvariables were combined and analyzed simultaneously by using the O'BrienRank Sum Method, as specified in the protocol. The results showed thatsubjects treated with 30DM/30Q had a statistically significant reductionin episodes of laughing and crying and an improvement in QOL and QORrelative to the subjects treated with DM (p=0.0041) or Q (p=0.0001)after adjustment for multiple comparisons. 30DM/30Q was statisticallysignificantly better that either DM or Q in improving pseudobulbaraffect, number of episodes of laughing and crying, QOL, and QOR insubjects with ALS.

The extent of exposure to study medication, in terms of number of dosestaken, is reported in Table 35. The mean days of exposure were verysimilar across all treatment groups.

TABLE 35 30DM/30Q DM Q Exposure Statistics^(a) (N = 70) (N = 33) (N =37) n 68 33 36 Mean 24.4 27.6 28.0 Std Dev 9.66 6.25 4.40 Median 29.029.0 29.0 Min/Max 3/32 7/33 5/32 ^(a)Exposure was calculated by usingthe date of the last dose of study drug minus the date of the first doseof study drug + 1.

Nausea was the most common adverse event experienced, and it afflictedmore subjects [twenty-three (32.9%)] in the 30DM/30Q group than ineither the DM [2 (6.1%)] or the Q [3 (8.1%)] groups. However, in the30DM/30Q group, nausea was judged to be mild or moderate in twenty ofthe twenty-three subjects, but it was judged to be at least possiblyrelated to treatment with 30DM/30Q in nineteen of the twenty-threesubjects. All instances of nausea in the DM and Q groups were mild ormoderate, and all but one was judged to be at least possibly related totreatment. Dizziness was also reported by more subjects [fourteen (20%)]in the 30DM/30Q group than in either the DM [five (15.2%)] or the Q [one(2.7%)] groups. All instances of this adverse event in all treatmentgroups were mild or moderate, and almost all were judged to be at leastpossibly related to treatment. Somnolence was the third event that wasreported by more subjects [nine (12.9%)] in the 30DM/30Q group than ineither the DM [one (3.0%)] or the Q [zero (0%)] groups. All instances ofthis adverse event in all treatment groups were mild or moderate, andalmost all were judged to be at least possibly related to treatment.Three subjects experienced loose stools as an adverse event, and all ofthem were in the DM group. All instances of the event were mild, and allwere judged to be related to treatment.

A total of twenty-two subjects withdrew from the study because ofadverse events; seventeen (24.3%) were in the 30DM/30Q group, two (6.1%)in the DM group, and three (8.1%) in the Q group. The seventeen subjectsin the 30DM/30Q group experienced fifty adverse events, and most ofthese [seventeen (34%)] were related to the nervous system. All of thesefifty events except four were mild or moderate, and all but one werejudged to be at least possibly related to treatment. One subject had asevere headache, one subject had severe nausea and severe vomiting, andone subject had severe respiratory failure. The subject died as a resultof the respiratory failure. This was judged not related to studymedication. The other two subjects recovered without sequelae.

In the DM group, there were seven adverse events experienced by twosubjects. All of these events except one were mild or moderate, and allwere judged to be related to treatment. One subject, who had six of theseven adverse events, experienced severe diarrhea; received appropriatedrug treatment for this condition; and recovered without sequelae.

Three subjects in the Q group experienced five adverse events. Onesubject had a severe kidney infection that was judged to be not relatedto treatment, and one subject had severe muscle cramping that was judgedto be related to treatment. Both of these subjects recovered withoutsequelae. All other adverse events were mild or moderate, and most werejudged to be not related to treatment.

Overall, there were four serious adverse events experienced by subjectsin this study. Three subjects in the 30DM/30Q group reported seriousadverse events, but only one of these discontinued taking the drug. Allthree of these serious adverse events were judged to be not related tothe study drug. The only other serious adverse event was experienced bya subject in the Q group. This subject continued on the study drug, andthe event was also judged to be not related to the study drug. There wasone death during the study; one subject in the 30DM/30Q group diedbecause of respiratory failure unrelated to study treatment.

There was no statistically significant change in hematology, clinicalchemistry, or urinalysis values from Baseline to Day 29 in any treatmentgroup, nor any statistically significant change among the treatmentgroups in any laboratory value except a significant increase in CPK inthe DM group relative to the 30DM/30Q group. There were no clinicallyrelevant changes from Baseline to Day 29 in systolic blood pressure,diastolic blood pressure, heart rate, or respiration. There were noclinically relevant changes from Baseline to Day 29 in the results ofphysical examinations. There was a statistically significant differencein the change from Baseline to Day 29 in VR and in the QT intervalbetween the 30DM/30Q and Q groups. However, these changes were so smallthat they were not clinically relevant. There was no statisticallysignificant difference among the treatment groups in QT_(c), PR, and QRSduration.

Since the nature, frequency, and intensity of the adverse events werewithin acceptable limits in this subject population, and there were noclinically relevant findings for any other safety variable, 30DM/30Q issafe in this subject population.

The CYP2D6 genotypes in each treatment group of the safety populationwere determined and are provided in Table 36. As defined in theStatistical Analysis Plan, the ITT population did not include poormetabolizers. Extensive metabolizer was the most prevalent genotype inall treatment groups in the ITT population.

TABLE 36 30DM/ 30Q DM Q (N = 70) (N = 33) (N = 37) Genotype n (%) n (%)n (%) Poor metabolizer 5 (7.2) 3 (9.1) 3 (8.1) Extensive metabolizer 61(88.4) 30 (90.9) 32 (86.5) Ultrarapid metabolizer 3 (4.3) 0 (0.0) 2(5.4)

Q in this combination product inhibits the rapid first-pass metabolismof DM. Therefore, it was expected that the concentrations of DM inplasma would be higher and the concentration of its metabolite, DX,would be lower in subjects who had received 30DM/30Q. The concentrationsof DM and DX in the group receiving 30DM/30Q and the group receiving DMare provided in Table 37.

TABLE 37 30DM/30Q DM N = 70 N = 33 P-values^(b) Statistics DM DX DM DXDM DX n 35 35 23 23 Mean 96.37 89.46 5.18 295.92 <0.0001 <0.0001 Std Dev46.71 52.25 4.97 143.21 Median 96.26 78.24 4.55 262.35 Min/Max1.07/212.40 8.17/235.27 0.35/15.81 101.07/526.65 ^(a)Only those subjectswhose time of blood collection was within 8 hours of the time of theirlast dose of study medication were included in this table. ^(b)P-valuefrom ANOVA with adjustment for treatment.

The mean DM concentration was 18.6-fold higher in the 30DM/30Q groupthan in the DM group, and the mean DX concentration was 3.3-fold lowerin the 30DM/30Q group than in the DM group. These differences were bothstatistically significant. The data for the levels in plasma of allsubjects show the same results as in those subjects whose blood wascollected within eight hours of the last dose of study medication.

The results of the study demonstrate that 30DM/30Q was statisticallysignificantly more effective than its components in the treatment ofpseudobulbar affect as indicated by the primary and all secondaryendpoints. Expected adverse events were reported, and no unexpectedsafety issues emerged. More subjects in the 30DM/30Q group had adverseevents than in either of the other groups, and seventeen subjects in the30DM/30Q group discontinued the study because of adverse events;however, all adverse events except four in the subjects who discontinuedwere mild or moderate. Only two of the seventeen subjects had severeadverse events (headache, nausea, vomiting), and these events, althoughdebilitating, resolved without sequelae. There were three subjectstreated with 30DM/30Q with serious events, and all of the events wereunrelated to this treatment. Furthermore, as the results of theassessments of QOL and QOR were markedly and statistically significantlybetter in the subjects treated with 30DM/30Q, the benefits of the drugoutweighed any discomfort caused by the adverse events. Therefore,30DM/30Q was very effective in treating pseudobulbar affect in ALSsubjects, and the drug was safe and well tolerated.

Clinical Study #5

The primary objective of this study was to evaluate the safety andtolerability of capsules containing dextromethorphan hydrobromide andquinidine sulfate (DM/Q) during an open-label, dose-escalation study tothe subject's maximum tolerated dose (MTD), not to exceed 120 mg DM/120mg Q per day. The secondary objective was to obtain a preliminaryassessment of the efficacy of DM/Q in the treatment of pain associatedwith diabetic neuropathy.

This was an open-label, dose-escalation study in subjects experiencingpain associated with diabetic neuropathy. After screening forinclusion/exclusion criteria, subjects underwent a washout period duringwhich all analgesics were discontinued. This was followed by twenty-ninedays of treatment with capsules containing 30 mg DM/30 mg Q, beginningwith one capsule per day and escalating approximately weekly to amaximum permitted dose of four capsules per day. Subjects who could nottolerate a dose level could return to the previous level; couldsubstitute a capsule containing 15 mg DM/30 mg Q; or, if they wereunable to tolerate the lowest dose level, could be discontinued from thestudy.

Subjects were screened for general health, includingelectrocardiography, within four weeks before Day 1 of dosing. The firstdose of DM/Q was administered at the clinic, and a restingelectrocardiogram was obtained one hour after this dose and interpretedon site. If the corrected QT interval (QT_(c)) determined in thispreliminary interpretation was not ≧450 msec for males or ≧470 msec forfemales, and the QT_(c) did not change from the screeningelectrocardiogram by more than 30 msec, the subject was issued studymedication to take as directed by the physician. The subject wasinstructed on the use of a daily diary to record study medication takenand scores from rating scales for sleep, present and average painintensity, and activity.

Subjects visited the clinic every two weeks during the four-weekduration of the study and were contacted by telephone during weekswithout clinic visits. At each subsequent study visit or weekly phonecall, the subjects were given the Pain Intensity Rating Scale and thePain Relief Rating Scale and were queried regarding any adverse eventsthat might have occurred since their previous visit. Subjects wereadministered the Peripheral Neuropathy Quality of Life (QOL) Instrumenton Days 1 and 29 (or the final visit). Blood samples were taken at thevisits on Day 15 and Day 29 to determine concentrations in plasma of DM,DX, and Q.

Subjects selected were 18 to 80 years of age, inclusive, and had aconfirmed diagnosis of diabetes mellitus. Subject had acceptableglycemic control, with total glycosylated hemoglobin (HbA1c) <12%, hadbeen on established diabetic therapy for at least 3 months, had aclinical diagnosis of distal symmetrical diabetic neuropathy, and haddaily pain associated with diabetic neuropathy for the previous 3months. Subjects scored moderate or greater 2) on the Pain IntensityRating Scale before receiving DM/Q on Day 1.

Every effort was made to continue each subject in the study. However, ifa subject decided to withdraw, all efforts were made to complete allassessments and an explanation of why the subject withdrew from thestudy was provided.

Subjects received capsules containing 30 mg DM/30 mg Q or 15 mg DM/30 mgQ in increasing dosages, to a maximum of 120 mg DM/120 mg Q. Studymedications were provided as hard gelatin capsules; Capsule A was opaqueorange, and Capsule B was opaque white. The contents of the capsules arelisted in Table 38.

TABLE 38 Amount (mg) Capsule A Capsule B^(a) Ingredient 30 mg DM/30 mg Q15 mg DM/30 mg Q Dextromethorphan 31.50^(b) 15.75^(c) hydrobromidemonohydrate USP (DM) Quinidine sulfate dihydrate 31.40^(d) 31.40^(d) USP(Q) Croscarmellose sodium NF 7.80 7.80 Microcrystalline cellulose NF94.00 101.87 Colloidal silicone dioxide NF 0.050 0.065 Lactosemonohydrate NF 94.00 101.88 Magnesium stearate NF 0.05 0.05 ^(a)Foroptional use if Capsule A was not tolerated. ^(b)Equivalent to 30.0 mgdextromethorphan hydrobromide. ^(c)Equivalent to 15.0 mgdextromethorphan hydrobromide. ^(d)Equivalent to 30.0 mg quinidinesulfate.

Subjects received capsules containing DM/Q in escalating doses, asindicated in Table 39. Subjects who could not tolerate a dose level werepermitted to return to the previous level, substitute a capsulecontaining 15 mg DM/30 mg Q, or be discontinued from the study if theywere unable to tolerate the lowest dose level.

TABLE 39 AM Dose PM Dose Total Daily Dose Number of DM Q Number of DM QNumber of DM Q Study Day Capsules (mg) (mg) Capsules (mg) (mg) Capsules(mg) (mg) 1 (in clinic) 0 0 0 1 30 30 1 30 30 2 to 3 0 0 0 1 30 30 1 3030  4 to 13 1 30 30 1 30 30 2 60 60 14 to 20 1 30 30 2 60 60 3 90 90 21to 29 2 60 60 2 60 60 4 120 120

Subjects could not take any disallowed medications during the study orfor one week (or two weeks, where applicable) before the start of dosingon Day 1. These medications included: amantadine; amitriptyline; anyantidepressant medication, including St. John's Wort; any monoamineoxidase inhibitor; analgesics (only acetaminophen could be used);captopril; cimetidine; carbonic anhydrase inhibitors; desipramine;dextromethorphan (OTC cough medicines); digoxin; diltiazem;erythromycin; fluoxetine; haloperidol; imipramine; itraconazole;ketoconazole; nortriptyline; paroxetine; quinidine or otherantiarrhythmic drugs; sodium bicarbonate; thiazide diuretics; andverapamil. If a subject was unable to complete the washout periodwithout analgesia, he/she was permitted to begin the dose-escalationphase of the study, provided that sufficient washout of otherdisallowed, non-pain medications had occurred. Daily, low-dose aspirinwas not considered an analgesic and was permitted for cardiacprophylaxis.

Acetaminophen was the only analgesic permitted as a rescue painmedication and was to be taken at the dosage specified on the packagelabel. Subjects were instructed to consult the study clinic beforetaking any medication, including over-the-counter (OTC) medications, andthey were counseled that acetaminophen-containing products that alsocontained other analgesics (e.g., codeine) or dextromethorphan should beavoided.

Subjects were instructed to bring unused study medication to the clinicon Day 15 and to return all unused study medication to the clinic at thefinal visit. Diary cards were collected from subjects at these visits.The percent of doses taken was calculated as the total number of dosestaken divided by the total number of doses prescribed, multiplied by100.

Safety was assessed by the following measurements: adverse events;clinical laboratory values; vital signs; physical examinations;electrocardiograms; and measurements of nerve conduction velocity.

Subjects underwent nerve conduction studies at Screening and on Day 29(or the final visit). Nerve conduction velocity was measured withsurface stimulation and recording. Bilateral sural nerve sensory studiesand a unilateral peroneal nerve motor study were performed or supervisedby a clinical electromyographer certified by the American Board ofElectrodiagnostic Medicine. Techniques were standardized to minimizevariability among electromyographers. Limb temperature was maintainedabove a standard temperature in all studies. Results were interpreted ata central reading laboratory.

Efficacy was assessed through the following instruments: Pain IntensityRating Scale; Diary Present Pain Intensity Scale; Pain Relief RatingScale; Diary Activity Rating Scale; Peripheral Neuropathy QOLInstrument; Diary Average Pain Rating Scale; and Diary Sleep RatingScale.

Score on the Pain Intensity Rating Scale was determined on Day 8, Day15, Day 22, and Day 29 (or the final visit). Subjects indicated theamount of pain experienced in the lower extremities within the previoustwenty-four hours by using a 5-point Likert scale (0=None, 1=Mild,2=Moderate, 3=Severe, 4=Extreme). Subjects were required to complete thePain Intensity Rating Scale at the clinic on Day 1, before entry intothe study and on Day 15 and Day 29 (or the final visit). The scale wasalso administered verbally in telephone calls to the subject duringweeks when no clinic visit was scheduled (Day 8 and Day 22).

The Pain Relief Rating Scale was completed on Day 8, Day 15, Day 22, andDay 29 (or the final visit). Subjects indicated the amount of painrelief experienced in the lower extremities relative to the end of thewashout/screening phase by using a 6-point Likert scale (−1=Worse,0=None, 1=Slight, 2=Moderate, 3=A lot, 4=Complete). Subjects wererequired to complete the scale at the clinic on Day 15 and Day 29 (orthe final visit). The Pain Relief Rating Scale was also administeredverbally in telephone calls to the subject during weeks when no clinicvisit was scheduled (Day 8 and Day 22).

The QOL score was obtained at the clinic on Day 1 and Day 29 (or thefinal visit). QOL was assessed by using the Peripheral Neuropathy QOLInstrument-97 as in Vickrey et al., Neurorehabi. Neural. Repair, 2000;14:93-104. This is a self-administered, health-related, QOL measure forperipheral neuropathy. It incorporates the Health Status Survey SF-36scale in its entirety and includes additional questions determined to beparticularly relevant to subjects with peripheral neuropathy.

The instrument comprises 21 subscales containing items about generalhealth issues, specific peripheral neuropathy issues, health symptoms orproblems, assessment of overall health, and feelings in general andabout health. All of the items use 3-, 4-, 5-, or 6-point categoricalrating scales, except for number of disability days, overall healthrating (0 to 100), and a yes/no question about sexual activity.

To analyze the QOL results, a scoring algorithm was used to convert thecategorical item ratings to appropriate percent ratings. The mostfavorable rating was 100%, the least favorable was 0%, and theintermediate percents were spaced at equal intervals, depending on thenumber of points in the scale (e.g., 0, 25, 50, 75, 100 for a 5-pointascending scale; 100, 50, 0 for a 3-point descending scale). Theconverted ratings for each item in a subscale were averaged to providethe subscale scores. All subscale scores were constructed so that ahigher value reflected a more favorable result. The composite QOL scorewas obtained by averaging all subscale scores, except for number ofdisability days.

The subject diary included a sleep rating scale and a present painintensity scale to be completed in the morning, and an activity ratingscale and an average pain rating scale to be completed in the evening.In the Sleep Rating Scale, subjects were instructed to circle the numberon a scale of 0 to 10 that best described the extent that pain hadinterfered with their sleep in the past 24 hours (0=Does not interfereand 10=Completely interferes). In the Present Pain Intensity Scale,subjects were instructed to circle the statement that best describedtheir present pain intensity: O—No Pain; 1—Mild; 2—Discomforting;3—Distressing; 4—Horrible; and 5—Excruciating. In the Activity RatingScale, subjects were instructed to circle the number on a scale of 0 to10 (the same as the Sleep Rating Scale) that best described the extentthat pain had interfered with their general activity in the past 24hours (0=Does not interfere and 10=Completely interferes). In theAverage Pain in Past 12 Hours Rating Scale, subjects were instructed tocircle the number on a scale of 0 to 10 (the same as the Sleep RatingScale) that best described their average pain intensity during the past12 hours (0=None and 10=Worst pain ever). The rating scales used asefficacy measures are well-established instruments in pain research, andthe Peripheral Neuropathy QOL instrument, in particular, containsmaterial that is specific for subjects with peripheral neuropathy.

Efficacy evaluations consisted of inferential analyses and summarystatistics, calculated on all subjects and on subjects categorized byMTD, for the following variables (except where noted): change frombaseline in the Pain Intensity Rating Scale score on Days 8, 15, 22, and29 (or the final visit); the Pain Relief Rating Scale score on Days 8,15, 22, and 29 (or the final visit); change from baseline in thecomposite score on the Peripheral Neuropathy Quality of Life Instrumenton Day 29 (or the final visit); Sleep Interference score calculated fromvalues recorded in the diary for the Sleep Rating Scale (the score forDay 15 was the average of the Sleep Rating Scale scores from the subjectdiary for Days 13, 14, and 15; the score for Day 29 was the average ofthe Day 27, 28, and 29 scores; and the Final Visit score was the averageof scores from the final 3 consecutive days of study treatment); DailyPresent Pain Intensity, Activity, Pain, and Sleep Rating scales,recorded in subject diaries; the percent of subjects experiencingimproved scores for each of the efficacy variables.

The disposition of subjects is provided in FIG. 3. Subjects areclassified by MTD group in this figure and in subsequent summary tablesand figures. Except for a subject with an MTD of 45 mg, who wasclassified with the 60-mg group (see below), subjects in the 30-, 60-,and 90-mg groups received the MTDs indicated. Subjects in the 120-mggroup tolerated this dose, which was the highest dose permitted in thestudy but is technically not an MTD. For brevity these groupings are allreferred to as “MTDs.”

Of the thirty-six subjects who were enrolled and received studymedication, thirty-three completed the study. One subject completed thestudy with an MTD of 45 mg DM. Because there was only one subject withthis MTD, this subject is included with the 60-mg MTD group in the datatables and in FIG. 3. The number of subjects in each MTD group andoverall in each study site is reported in Table 40.

TABLE 40 MTD (mg) Site 30 45 60 90 120 Total 01 1 0 0 0 4 5 02 1 0 0 0 34 03 0 0 3 0 0 3 04 2 1 2 2 5 12 05 1 0 0 0 11 12 Total 5 1 5 2 23 36

Only one population was used in the data analyses. Analyses andsummaries were performed by using all 36 subjects who took studymedication. The demographic characteristics of the study population arereported in Table 41.

TABLE 41 Maximum Tolerated Dose (mg)^(a) 30^(b) 60^(c) 90 120 TotalCharacteristic (N = 5) (N = 6) (N = 2) (N = 23) (N = 36) Age (years) n 56 2 23 36 Mean 62.2 57.7 57.0 57.1 57.9 SD^(d) 10.99 8.14 9.90 11.9910.94 Median 65.0 59.0 57.0 56.0 57.0 Min/Max 49/77 45/67 50/64 22/7822/78 Gender, n (%) Male 4 (80.0) 3 (50.0) 1 (50.0) 11 (47.8) 19 (52.8)Female 1 (20.0) 3 (50.0) 1 (50.0) 12 (52.2) 17 (47.2) Race, n (%)Caucasian 3 (60.0) 5 (83.3)  2 (100.0) 15 (65.2) 25 (69.4) Black 1(20.0) 0 (0.0)  0 (0.0)  2 (8.7) 3 (8.3) Asian 0 (0.0)  0 (0.0)  0(0.0)  0 (0.0) 0 (0.0) Other^(e) 1 (20.0) 1 (16.7) 0 (0.0)   6 (26.1)  8(22.2) ^(a)Maximum Tolerated Dose is the last dose taken when thesubject left or completed the study. ^(b)This group included subjectswho took two 15-mg capsules/day as well as subjects who took one 30-mgcapsule/day. ^(c)This group included one subject whose MTD was 45 mg.^(d)SD = Standard deviation. ^(e)All of the subjects in the category“Other” were described as Hispanic.

The history of the subjects' diabetic neuropathy is summarized in Table42.

TABLE 42 Maximum Tolerated Dose (mg)^(a) 30^(b) 60^(c) 90 120 TotalCharacteristic (N = 5) (N = 6) (N = 2) (N = 23) (N = 36) Duration ofDiabetic Neuropathy (years) n 5 6 2 23 36 Mean 3.9 3.8 3.2 5.3 4.7 SD4.30 5.01 0.21 6.35 5.63 Median 2.5 0.9 3.2 2.4 2.5 Min/Max 0.6/11.40.2/10.4 3.0/3.3 0.5/24.3 0.2/24.3 Duration of Daily Pain (months) n 5 62 23 36 Mean 30.2 30.0 9.0 38.0 34.0 SD 30.99 17.47 4.24 46.32 39.42Median 24.0 27.0 9.0 18.0 24.0 Min/Max 7/84 7/60  6/12  4/180  4/180^(a)Maximum Tolerated Dose is the last dose taken when the subject leftor completed the study. ^(b)This group included subjects who took two15-mg capsules/day as well as subjects who took one 30-mg capsule/day.^(c)This group included one subject whose MTD was 45 mg.

Subjects enrolled in the study had received their diagnosis of diabeticneuropathy a minimum of 0.2 years and a maximum of 24.3 years previously(median of 2.5 years). Subjects had experienced daily pain from theirdiabetic neuropathy for a minimum of four months and a maximum of 180months/15.0 years (median of 24.0 months/2.0 years).

Concomitant medications were reported for up to 30 days before the studyand throughout the treatment period. Concomitant medications reported byat least 10% of subjects overall are listed in Table 43 by WHO term.

TABLE 43 Maximum Tolerated Dose (mg)^(a) 30^(b) 60^(c) 90 120 Total DrugCategory (N = 5) (N = 6) (N = 2) (N = 23) (N = 36) WHO Preferred Term n(%) n (%) n (%) n (%) n (%) Analgesics Paracetamol (acetaminophen) 0(0.0) 1 (16.7) 1 (50.0) 2 (8.7)  4 (11.4) ACE inhibitors Lisinopril 0(0.0) 1 (16.7) 0 (0.0) 4 (17.4) 5 (14.3) Diuretics Furosemide 0 (0.0) 1(16.7) 0 (0.0) 4 (17.4) 5 (14.3) Hydrochlorothiazide 2 (40.0) 1 (16.7) 0(0.0) 2 (8.7)  5 (14.3) Anticoagulants Acetylsalicylic acid^(d) 1 (20.0)2 (33.3) 1 (50.0) 6 (26.1) 10 (28.6)  Lipid-lowering agents Atorvastatin1 (20.0) 0 (0.0) 0 (0.0) 5 (21.7) 6 (17.1) Antidiabetic agentsGlibenclamide 1 (20.0) 1 (16.7) 1 (50.0) 5 (21.7) 8 (22.9) Glipizide 0(0.0) 2 (33.3) 0 (0.0) 2 (8.7)  4 (11.4) Insulin 2 (40.0) 0 (0.0) 0(0.0) 3 (13.0) 5 (14.3) Insulin human injection, isophane 0 (0.0) 2(33.3) 0 (0.0) 2 (8.7)  4 (11.4) Metformin 1 (20.0) 1 (16.7) 1 (50.0) 6(26.1) 9 (25.7) Metformin hydrochloride 0 (0.0) 1 (16.7) 0 (0.0) 6(26.1) 7 (20.0) Oral antidiabetics 4 (80.0) 1 (16.7) 1 (50.0) 11 (47.8) 17 (48.6)  Nutritional supplements Ascorbic acid 1 (20.0) 0 (0.0) 1(50.0) 2 (8.7)  4 (11.4) Calcium 1 (20.0) 1 (16.7) 1 (50.0) 3 (13.0) 6(17.1) Multivitamins 0 (0.0) 0 (0.0) 1 (50.0) 3 (13.0) 4 (11.4)Tocopherol 1 (20.0) 0 (0.0) 0 (0.0) 4 (17.4) 5 (14.3) OtherLevothyroxine sodium 0 (0.0) 0 (0.0) 1 (50.0) 3 (13.0) 4 (11.4)Sildenafil citrate 1 (20.0) 3 (50.0) 0 (0.0) 0 (0.0)  4 (11.4) All othertherapeutic products 1 (20.0) 1 (16.7) 0 (0.0) 2 (8.7)  4 (11.4)^(a)Maximum Tolerated Dose is the last dose taken when the subject leftor completed the study. ^(b)This group included subjects who took two15-mg capsules/day as well as subjects who took one 30-mg capsule/day.^(c)This group included one subject whose MTD was 45 mg. ^(d)Allsubjects who took acetylsalicylic acid concurrently with their studytreatment did so for the indication of cardiac prophylaxis and notanalgesia.

Use of rescue medication (acetaminophen) was limited. Only four subjectstook rescue medication: one took acetaminophen on twenty-eight out oftwenty-nine study days, one on sixteen study days, and two on only onestudy day. Overall, there was little use of rescue medication for painduring this study; subjects took rescue medication on an average of 1.3days each (4.5% of study days).

The extent of exposure to study medication is in Table 44.

TABLE 44 Maximum Tolerated Dose (mg)^(a) Exposure 30^(b) 60^(c) 90 120Total Statistic (N = 5) (N = 6) (N = 2) (N = 23) (N = 36) Amount of DMTaken (mg) n 4 6 2 23 35 Mean 960.0 1442.5 2160 2321.7 2006.1 SD 667.68682.42 42.43 121.94 609.17 Median 1095 1530 2160 2310 2310 Min/Max30/1620 270/2370 2130/2190 2010/2640 30/2640 Amount of Q Taken (mg) n 46 2 23 35 Mean 1200.0 1525.0 2160.0 2321.7 2047.7 SD 781.15 682.90 42.43121.94 562.49 Median 1575 1620 2160 2310 2310 Min/Max 30/1620 270/23702130/2190 2010/2640 30/2640 Days on Study Medication^(d) n 4 6 2 23 35Mean 22.0 25.3 29.0 29.0 27.6 SD 14.00 9.48 0.00 1.22 6.13 Median 29 2929 29 29 Min/Max 1/29  6/30 29/29 25/32 1/32  ^(a)Maximum Tolerated Doseis the last dose taken when the subject left or completed the study.^(b)This group included subjects who took two 15-mg capsules/day as wellas subjects who took one 30-mg capsule/day. ^(c)This group included onesubject whose MTD was 45 mg. ^(d)Number of days on study medication wascalculated by using the date of the last dose of study drug minus thedate of the first dose of study drug, plus 1.

The number of subjects with adverse events is reported in Table 45.

TABLE 45 Maximum Tolerated Dose (mg)^(a) 30^(b) 60^(c) 90 120 Total (N =5) (N = 6) (N = 2) (N = 23) (N = 36) Category n (%) n (%) n (%) n (%) n(%) Adverse Events 4 (80.0)  6 (100.0) 2 (100.0) 19 (82.6) 31 (86.1)Serious 1 (20.0) 2 (33.3) 0 (0.0)  0 (0.0) 3 (8.3) Adverse EventsDiscontinued 1 (20.0) 1 (16.7) 0 (0.0)  0 (0.0) 2 (5.6) Because ofAdverse Events ^(a)Maximum Tolerated Dose is the last dose taken whenthe subject left or completed the study. ^(b)This group includedsubjects who took two 15-mg capsules/day as well as subjects who tookone 30-mg capsule/day. ^(c)This group included one subject whose MTD was45 mg.

The majority of subjects had at least one adverse event during thestudy. Nearly all of the adverse events were mild or moderate inintensity. Four subjects had a total of seven serious adverse events.Two subjects had four severe adverse events. One subject had severeinsomnia and recovered with a reduced dose of study drug; and onesubject had severe fatigue and severe rigors, and recovered withoutchange in study drug. Adverse events experienced by at least 5% ofsubjects overall are reported in Table 46.

TABLE 46 Maximum Tolerated Dose (mg)^(a) 30^(b) 60^(c) 90 120 TotalAdverse Event (N = 5) (N = 6) (N = 2) (N = 23) (N = 36) Preferred Term n(%) n (%) n (%) n (%) n (%) Alanine aminotransferase 0  (0.0) 0  (0.0) 0 (0.0) 2  (8.7) 2  (5.6) increased Appetite decreased NOS^(d) 1 (20.0) 0 (0.0) 0  (0.0) 1  (4.3) 2  (5.6) Back pain 0  (0.0) 0  (0.0) 0  (0.0) 2 (8.7) 2  (5.6) Constipation 0  (0.0) 0  (0.0) 0  (0.0) 3 (13.0) 3 (8.3) Diarrhea NOS 2 (40.0) 0  (0.0) 1 (50.0) 3 (13.0) 6 (16.7)Dizziness (exc. vertigo) 1 (20.0) 2 (33.3) 1 (50.0) 5 (21.7) 9 (25.0)Dry mouth 2 (40.0) 1 (16.7) 0  (0.0) 1  (4.3) 4 (11.1) Fatigue 0  (0.0)3 (50.0) 1 (50.0) 2  (8.7) 6 (16.7) Flatulence 2 (40.0) 0  (0.0) 0 (0.0) 0  (0.0) 2  (5.6) Gamma-glutamyl- 0  (0.0) 0  (0.0) 0  (0.0) 2 (8.7) 2  (5.6) transferase increased Headache NOS 1 (20.0) 3 (50.0) 1(50.0) 4 (17.4) 9 (25.0) Insomnia NEC^(e) 1 (20.0) 0  (0.0) 1 (50.0) 1 (4.3) 3  (8.3) Libido decreased 1 (20.0) 0  (0.0) 0  (0.0) 1  (4.3) 2 (5.6) Nausea 2 (40.0) 2 (33.3) 1 (50.0) 5 (21.7) 10 (27.8) Somnolence 2(40.0) 0  (0.0) 1 (50.0) 3 (13.0) 6 (16.7) Syncope 0  (0.0) 0  (0.0) 0 (0.0) 2  (8.7) 2  (5.6) Tinnitus 0  (0.0) 0  (0.0) 1 (50.0) 1  (4.3) 2 (5.6) Upper respiratory 0  (0.0) 1 (16.7) 0  (0.0) 2  (8.7) 3  (8.3)tract infection NOS ^(a)Maximum Tolerated Dose is the last dose takenwhen the subject left or completed the study. ^(b)This group includedsubjects who took two 15-mg capsules/day as well as subjects who tookone 30-mg capsule/day. ^(c)This group included one subject whose MTD was45 mg. ^(d)NOS = Not otherwise specified. ^(e)NEC = Not elsewhereclassified.

Nausea was the most common adverse event experienced, occurring in 10(27.8%) subjects overall. Nausea was judged to be mild in seven subjects(19.4%) and moderate in three subjects. Nausea was judged to be at leastpossibly related to treatment in all cases. There was no apparentrelationship between the maximum tolerated dose and the occurrence,severity, or relationship of nausea to study drug. Dizziness wasreported by nine subjects (25.0%) overall. Dizziness was mild in sixsubjects (16.7%) and moderate in three subjects (8.3%). For the majorityof these subjects (seven versus two), dizziness was judged to be atleast possibly related to treatment. Nine subjects (25.0%) reportedheadache. All instances of this adverse event were mild or moderate, andthe majority (six out of nine) were judged to be possibly related totreatment. Two subjects withdrew from the study because of adverseevents. One subject, with an MTD of 30 mg, withdrew after one dose ofstudy medication because of a pre-existing colon polyp that requiredresection. The other subject, with an MTD of 60 mg, withdrew on Day 6because of recurring, intermittent chest pain.

One subject had an exacerbation of Chronic Obstructive Pulmonary Disease(COPD) at the time of his final visit on Day 29, was counseled tocontact his primary care physician, and was hospitalized that day. OnDay 33 the subject died suddenly while still in the hospital; hisprimary care physician indicated myocardial infarction and arrhythmia asthe presumed causes of death. The investigator indicated that thissubject's COPD exacerbation was not related to study drug and that hismyocardial infarction and arrhythmia were unlikely to be related tostudy drug.

One subject, whose MTD was 60 mg, had a history of hypertension (fouryears) and atypical chest pain (two years). She developed recurring,intermittent chest pain on Day 6 and was admitted to the hospital on Day7. She discontinued study medication. All tests for cardiac causes werenegative. The subject recovered on Day 8, was discharged on Day 9, andreturned to work on Day 10. The underlying cause of this subject's chestpain was unclear and her chest pain was possibly related to study drug.

All of the clinical laboratory adverse events were mild or moderate inintensity. Two subjects had elevated creatine kinase values, twosubjects had elevated liver enzyme values accompanied by otherabnormalities, and one subject had blood in the stool. Two subjectsrecovered from all of their clinical laboratory adverse events, onesubject did not recover, and the outcome of the adverse events wasunknown for 2 subjects because they did not return to the study clinicfor follow-up testing. The majority of these adverse events were judgedto have a “possible” relationship to study drug. None of the clinicallaboratory adverse events were serious adverse events, and none requireda dosage reduction or discontinuation of study drug.

There were no clinically relevant changes from Baseline to Day 29 insystolic blood pressure, diastolic blood pressure, heart rate, orrespiration at any MTD. There were no clinically relevant changes in theresults of physical examinations during study treatment. There was noclinically relevant difference among the MTD groups in mean QT, QT_(c),PR, or QRS duration, or change in any electrocardiogram values duringthe study.

There were no meaningful differences in motor conduction velocities inthe distal peroneal nerve segment, between the fibular head and ankle,for each of the 4 MTD groups at Screening. The mean baseline motorconduction velocity was 39.2 m/sec (range of 26.6 to 49.0 m/sec). Therewere also no differences between the change in motor nerve conductionfrom Screening to the final visit for each of the MTDs. The mean changein motor conduction velocity in the fibular head-to-ankle segment forthe total study population was 0.8 m/sec (range of −4.0 to +7.7 m/sec).There was a marked slowing of conduction velocity in the proximalperoneal nerve segment, between the fibular head and popliteal fossa,for the 120-mg MTD group (−6.7 m/sec) and for the total study population(−5.5 m/sec). However, this can be explained by the unusually high nerveconduction velocity measured in this segment at Screening (mean of 47.6m/sec and range of 21.7 to 66.7 m/sec in the 120-mg MTD group). Twelveof the twenty-three subjects in this group had baseline motor conductionvelocities greater than 50 m/sec; these unusually high values for thispopulation could reflect the short distance over which this segment ofthe nerve was stimulated, which could have resulted in measurementerrors.

Any significant slowing of nerve conduction velocity would manifest moreseverely in distal segments of nerve, as is seen electrophysiologicallyin diabetic neuropathy, because the frequency of this conditionincreases with length of the nerve pathway. For these reasons, theproximal conduction velocities measured in this study were interpretedas an assessment of the presence of focal peroneal neuropathy at thefibular head, and not as a measure of safety or tolerance of the studymedication. In conclusion, there was no electrophysiologic evidence tosuggest that the analgesic property of DM/Q is due to a toxic effect onperipheral nerves.

The combination of DM/Q, at daily doses from 30 mg DM/30 mg Q to 120 mgDM/120 mg Q, was safe and well tolerated in this subject population. Thenature, frequency, and intensity of adverse events were withinacceptable limits. Although five subjects had at least one laboratoryadverse event, all were mild or moderate in intensity and none requireda change in study drug dosing. There were no findings of clinicalconcern for vital signs, physical examinations, or electrocardiographicresults. No clinically significant changes in nerve conduction velocitywere detected. Study treatment was well tolerated; and the majority ofsubjects had an MTD of the highest permissible dose (120 mg DM/120 mgQ).

The frequencies of subjects with each pain intensity score at each timepoint are reported in Table 47.

TABLE 47 Pain Intensity Rating Scale Score 0 1 2 3 4 Study Visit (None)(Mild) (Moderate) (Severe) (Extreme) Total Day 1   0 (0.0)  0 (0.0) 20(55.6) 15 (41.7) 1 (2.8) 36 (100.0) Day 8   3 (9.1)  14 (42.4) 14 (42.4)2 (6.1) 0 (0.0) 33 (100.0) Day 15  5 (15.2) 18 (54.6) 10 (30.3) 0 (0.0)0 (0.0) 33 (100.0) Day 22 10 (30.3) 15 (45.5)  6 (18.2) 2 (6.1) 0 (0.0)33 (100.0) Final Visit 14 (40.0) 14 (40.0)  5 (14.3) 2 (5.7) 0 (0.0) 35(100.0)

On Day 1 (baseline), all subjects had a pain intensity of 2 (moderate)or greater, as specified in the protocol inclusion criteria. By thefinal visit, only a minority of subjects (20.0%) had moderate or greaterpain, and 40% reported no pain.

The changes from baseline in the Pain Intensity Rating Scale scores arereported in Table 48.

TABLE 48 Maximum Tolerated Dose (mg)^(a) P-value 30^(b) 60^(c) 90 120Total Baseline Visit Statistic (N = 5) (N = 6) (N = 2) (N = 23) (N = 36)and MTD^(d) Baseline^(e) Day 8 n 3 5 2 23 33 0.9525 <0.0001 Mean −1.0−1.0 −0.5 −1.1 −1.0 SD 1.00 1.00 0.71 0.90 0.88 Median −1.0 −1.0 −0.5−1.0 −1.0 Min/Max −2/0 −2/0 −1/0 −3/0 −3/0 Day n 3 5 2 23 33 0.4858<0.0001 15 Mean −0.3 −1.8 −0.5 −1.4 −1.3 SD 0.58 0.45 0.71 0.84 0.85Median 0.0 −2.0 −0.5 −1.0 −1.0 Min/Max −1/0 −2/−1 −1/0 −3/0 −3/0 Day n 35 2 23 33 0.2053 <0.0001 22 Mean −0.3 −1.6 −1.5 −1.6 −1.5 SD 0.58 0.550.71 1.08 1.00 Median 0.0 −2.0 −1.5 −2.0 −2.0 Min/Max −1/0 −2/−1 −2/−1−3/1 −3/1 Day n 3 5 2 22 32 0.1628 <0.0001 29 Mean −0.7 −1.6 −2.5 −1.8−1.7 SD 0.58 0.55 0.71 0.96 0.92 Median −1.0 −2.0 −2.5 −2.0 −2.0 Min/Max−1/0 −2/−1 −3/−2 −3/0 −3/0 Final n 4 6 2 23 35 0.0348 <0.0001 Visit Mean−0.5 −1.5 −2.5 −1.8 −1.6 SD 0.58 0.55 0.71 0.95 0.94 Median −0.5 −1.5−2.5 −2.0 −2.0 Min/Max −1/0 −2/−1 −3/−2 −3/0 −3/0 ^(a)Maximum ToleratedDose is the last dose taken when the subject left or completed thestudy. ^(b)This group included subjects who took two 15-mg capsules/dayas well as subjects who took one 30-mg capsule/day. ^(c)This groupincluded one subject whose MTD was 45 mg. ^(d)P-value for MTD from aregression model that models the efficacy variable as a function of bothbaseline score and MTD. ^(e)P-value for mean change in score from aregression model that models the efficacy variable as a function ofbaseline score.

Mean scores on the Pain Intensity Rating Scale decreased betweenbaseline and each subsequent visit for subjects overall. This decreasewas highly significant (all p-values<0.0001). For the change frombaseline to the final visit, the score decreases were significantlyrelated to MTD (p=0.0348), but there was no significant effect of MTD onscores for any of the other visits (all p-values≧0.1628).

Frequencies of subjects with each pain relief score at each study visitare reported in Table 49.

TABLE 49 Pain Relief −1 0 1 2 3 4 Study Visit (Worse) (None) (Slight)(Moderate) (A Lot) (Complete) Total Day 8 0 (0.0) 3 (9.1) 6 (18.2) 13(39.4)   8 (24.2) 3 (9.1)  33 (100.0) Day 15 0 (0.0) 1 (3.0) 5 (15.2) 6(18.2) 18 (54.6) 3 (9.1)  33 (100.0) Day 22 0 (0.0) 1 (3.0) 5 (15.2) 4(12.1) 17 (51.5) 6 (18.2) 33 (100.0) Final Visit 0 (0.0) 1 (2.9) 6(17.7) 5 (14.7) 13 (38.2) 9 (26.5) 34 (100.0)

In general, pain relief scores increased during the study. At Day 8,only 33.3% of subjects reported “a lot” or “complete” pain relief; bythe final visit, the majority (64.7%) did so. No subject reported“worse” pain compared to baseline at any visit, and only 1 subjectreported “None” at any visit after Day 8.

Summary statistics for Pain Relief Scale scores are reported in Table50.

TABLE 50 Maximum Tolerated Dose (mg)^(a) P-value 30^(b) 60^(c) 90 120Total Difference Visit Statistic (N = 5) (N = 6) (N = 2) (N = 23) (N =36) MTD^(d) from 0^(e) Day 8 n 3 5 2 23 33 0.4880 <0.0001 Mean 2.7 2.02.0 2.0 2.1 SD 0.58 1.58 0.00 1.09 1.09 Median 3.0 2.0 2.0 2.0 2.0Min/Max 2/3 0/4 2/2 0/4 0/4 Day n 3 5 2 23 33 0.7953 <0.0001 15 Mean 2.02.8 2.5 2.5 2.5 SD 1.00 1.10 0.71 0.99 0.97 Median 2.0 3.0 2.5 3.0 3.0Min/Max 1/3 1/4 2/3 0/4 0/4 Day n 3 5 2 23 33 0.6110 <0.0001 22 Mean 2.32.6 3.0 2.7 2.7 SD 0.58 1.14 0.00 1.15 1.05 Median 2.0 3.0 3.0 3.0 3.0Min/Max 2/3 1/4 3/3 0/4 0/4 Day n 3 5 2 22 32 0.6263 <0.0001 29 Mean 2.32.6 3.5 2.7 2.7 SD 1.15 1.14 0.71 1.20 1.14 Median 3.0 3.0 3.5 3.0 3.0Min/Max 1/3 1/4 3/4 0/4 0/4 Final n 3 6 2 23 34 0.7958 <0.0001 VisitMean 2.3 2.7 3.5 2.7 2.7 SD 1.15 1.03 0.71 1.23 1.15 Median 3.0 3.0 3.53.0 3.0 Min/Max 1/3 1/4 3/4 0/4 0/4 ^(a)Maximum Tolerated Dose is thelast dose taken when the subject left or completed the study. ^(b)Thisgroup included subjects who took two 15-mg capsules/day as well assubjects who took one 30-mg capsule/day. ^(c)This group included onesubject whose MTD was 45 mg. ^(d)P-value for MTD from a regression modelthat models the efficacy variable as a function of MTD. ^(e)P-value froma t-test testing that the mean of the total column is significantlydifferent from 0.

Mean scores on the Pain Relief Rating Scale increased significantly fromthe first assessment on Day 8 to each subsequent visit for subjectsoverall (all p-values<0.0001). There was no significant effect of MTD onpain relief scores at any visit (all p-values≧0.4880).

The change from baseline in the composite score from the PeripheralNeuropathy QOL Instrument is reported in Table 51.

TABLE 51 P-value Maximum Tolerated Dose (mg)^(a) Baseline Visit/ 30^(b)60^(c) 90 120 Total and Variable Statistic N = 5) (N = 6) (N = 2) (N =23) (N = 36) MTD^(d) Baseline^(e) Day 1 n 4 6 2 23 35 N/A^(f) N/A(Baseline)/ Mean 61.3 69.7 72.8 63.7 65.0 Score SD 15.26 13.68 0.1813.48 13.26 Median 60.8 66.8 72.8 65.3 66.7 Min/Max 47.1/76.4 49.8/86.972.7/72.9 35.6/87.2 35.6/87.2 Day 29/ n 3 5 2 22 32 N/A N/A Score Mean68.3 75.7 79.0 75.5 75.0 SD 13.38 15.88 4.68 9.93 10.82 Median 66.3 79.979.0 75.4 76.5 Min/Max 56.0/82.6 49.1/91.8 75.7/82.3 51.4/88.5 49.1/91.8Day 29/ n 3 5 2 22 32 0.1397 <0.0001 Change Mean 2.4 8.8 6.2 12.1 10.3from SD 10.87 13.35 4.85 10.77 10.95 Baseline Median 6.9 10.7 6.2 12.810.4 Min/Max −10.1/10.2 −6.8/27.7 2.7/9.6 −10.2/34.5 −10.2/34.5 FinalVisit/ n 3 6 2 23 34 N/A N/A Score Mean 68.3 77.6 79.0 75.4 75.4 SD13.38 14.99 4.68 9.71 10.71 Median 66.3 80.0 79.0 75.1 76.5 Min/Max56.0/82.6 49.1/91.8 75.7/82.3 51.4/88.5 49.1/91.8 Final Visit/ n 3 6 223 34 0.1828 <0.0001 Change Mean 2.4 7.9 6.2 11.6 9.8 from SD 10.8712.11 4.85 10.76 10.78 Baseline Median 6.9 7.2 6.2 12.7 9.9 Min/Max−10.1/10.2 −6.8/27.7 2.7/9.6 −10.2/34.5 −10.2/34.5 ^(a)Maximum ToleratedDose is the last dose taken when the subject left or completed thestudy. ^(b)This group included subjects who took two 15-mg capsules/dayas well as subjects who took one 30-mg capsule/day. ^(c)This groupincluded one subject whose MTD was 45 mg. ^(d)P-value for MTD from aregression model that models the efficacy variable as a function of bothbaseline score and MTD. ^(e)P-value for mean change in score from aregression model that models the efficacy variable as a function ofbaseline score. ^(f)N/A = Not applicable.

Mean composite scores on the Peripheral Neuropathy QOL Instrumentincreased (i.e., improved) significantly from Day 1 (baseline) to Day 29and to the final visit for subjects overall (both p-values<0.0001).Change from baseline to either Day 29 or the final visit was not relatedto MTD (all p-values≧0.1837).

P-values for change from baseline to the final visit in individual QOLscales are reported in Table 52.

TABLE 52 Scale P-value Scale P-value Physical Functioning 0.0012 GeneralHealth Perceptions <0.0001 Role Limitations 0.0003 Sleep <0.0001Disease-Targeted Pain <0.0001 Social Functioning <0.0001 Energy/Fatigue0.0001 Sexual Function 0.7714 Upper Extremities 0.0007 Health Distress<0.0001 Balance 0.0001 Severity 0.0129 Self Esteem 0.1258 DisabilityDays 0.1096 Emotional Well Being 0.0277 Health Change 0.0001 Stigma0.7851 Overall Health Rating 0.0064 Cognitive Function 0.0313Satisfaction with Sexual 0.3413 Functioning Emotional Role 0.2956Limitations ^(a)P-value for the change from baseline. A regression modelwas used to test whether the mean baseline value was different from themean value at the final visit.

The majority of individual QOL scale items improved significantlybetween baseline and the final visit (15/21, 74.1%).

Sleep interference scores, calculated for Day 15, Day 29, and the finalvisit, are reported in Table 53.

TABLE 53 Maximum Tolerated Dose (mg)^(b) P- 30^(c) 60^(d) 90 120 Totalvalue Visit Statistic (N = 5) (N = 6) (N = 2) (N = 23) (N = 36) MTD^(e)Day n 3 5 2 23 33 0.8509 15 Mean 1.4 2.2 2.2 1.8 1.8 SD 1.35 1.66 0.711.64 1.54 Median 1.7 2.0 2.2 1.3 1.7 Min/Max 0/3 0/4 2/3 0/5 0/5 Day n 35 2 22 32 0.1405 29 Mean 1.6 2.5 0.2 1.2 1.4 SD 1.35 2.09 0.24 1.29 1.47Median 1.3 2.0 0.2 0.7 0.8 Min/Max 0/3 0/5 0/0 0/4 0/5 Final n 3 5 2 2333 0.1077 Visit Mean 1.6 2.5 0.2 1.1 1.3 SD 1.35 2.09 0.24 1.20 1.41Median 1.3 2.0 0.2 0.7 1.0 Min/Max 0/3 0/5 0/0 0/4 0/5 ^(a)The score forDay 15 is the average of the Sleep Rating Scale scores from the subjectdiary for Days 13, 14, and 15; the score for Day 29 is the average ofthe Day 27, 28, and 29 scores; and the Final Visit score is the averageof the final 3 consecutive days of study treatment. ^(b)MaximumTolerated Dose is the last dose taken when the subject left or completedthe study. ^(c)This group included subjects who took two 15-mgcapsules/day as well as subjects who took one 30-mg capsule/day.^(d)This group included one subject whose MTD was 45 mg. ^(e)P-value forMTD from a regression model that models the efficacy variable as afunction of MTD.

Mean sleep interference scores declined during the study, indicatingdecreasing interference of the subjects' pain with their sleep. Therewas no significant effect of MTD on sleep interference scores at anyvisit (all p values≧0.1077). Results from the Sleep Rating Scale areplotted by study day in FIG. 4. Sleep scores decreased significantly(regression p<0.001) from Day 2 to the final study day (the lower thescore, the less pain was judged to interfere with sleep).

Results from the Present Pain Intensity Rating Scale are plotted bystudy day in FIG. 5. Present Pain Intensity scores decreasedsignificantly (regression p<0.001) from Day 2 to the final study day.Results from the Activity Rating Scale are plotted by study day in FIG.6. Activity scores decreased significantly (regression p<0.001) from Day1 to the final study day (the lower the score, the less pain was judgedto interfere with general activity). Results from the Pain Rating Scaleare plotted by study day in FIG. 7. Scores for average pain over theprevious twelve hours decreased significantly (regression p<0.001) fromDay 1 to the final study day. An improvement in efficacy score wasdefined as an improvement from the first recorded value to the lastrecorded value, except for the Pain Relief Rating Scale, where animprovement was defined as a value>0 for the last recorded value. Thefrequencies of subjects whose score improved during the study arepresented for each efficacy measure in Table 54.

TABLE 54 Maximum Tolerated Dose (mg)^(b) 30^(c) 60^(d) 90 120 Total (N =5) (N = 6) (N = 2) (N = 23) (N = 36) P-value Efficacy Variable n (%) n(%) n (%) n (%) n (%) MTD^(e) 50%^(f) Pain Intensity Rating Scale 2(50.0)  6 (100.0) 2 (100.0) 21 (91.3) 31 (88.6) 0.1698 <0.0001 PainRelief Rating Scale 3 (100.0) 5 (100.0) 2 (100.0) 22 (95.7) 32 (97.0)0.9419 <0.0001 QOL Composite Score 2 (66.7)  5 (83.3)  2 (100.0) 19(82.6) 28 (82.4) 0.6877 0.0002 Sleep Rating Scale (Diary) 3 (100.0) 5(83.3)  2 (100.0) 20 (87.0) 30 (88.2) 0.7222 <0.0001 Present PainIntensity Rating Scale 2 (66.7)  3 (50.0)  2 (100.0) 16 (69.6) 23 (67.6)0.5877 0.0396 (Diary) Activity Rating Scale (Diary) 2 (50.0)  5 (83.3) 2 (100.0) 20 (87.0) 29 (82.9) 0.1668 0.0001 Pain Rating Scale (Diary) 3(75.0)  5 (83.3)  2 (100.0) 20 (87.0) 30 (85.7) 0.5772 <0.0001 ^(a)Animprovement in efficacy score is an improvement from the first recordedvalue to the last recorded value, except for the Pain Relief RatingScale, where an improvement is a value > 0 for the last recorded value.^(b)Maximum Tolerated Dose is the last dose taken when the subject leftor completed the study. ^(c)This group included subjects who took two15-mg capsules/day as well as subjects who took one 30-mg capsule/day.^(d)This group included one subject whose MTD was 45 mg. ^(e)P-value forMTD from a regression model that models improvement in the efficacyvariable as a function of MTD. ^(f)P-value from a test that the totalpercent of subjects whose score improved = 50%.

A significant proportion of subjects improved during the study in everyefficacy measure (all p-values<0.0396). Improvement was not related toMTD for any of the efficacy measures (all p-values≧0.1668).

Subjects treated with open-label DM/Q, in the dose range of 30 mg DM/30mg Q to 120 mg DM/120 mg Q, reported a statistically significantreduction in pain from diabetic peripheral neuropathy and in the extentto which this pain interfered with general activity and sleep. Subjectsreceiving this treatment also experienced statistically significantimprovement in their QOL.

The CYP2D6 phenotypes of subjects, based upon their genotype results,are summarized in Table 55. There were no intermediate or ultra-rapidmetabolizers in this study population.

TABLE 55 Maximum Tolerated Dose (mg)^(a) 30^(b) 60^(c) 90 120 Total (N =5) (N = 6) (N = 2) (N = 23) (N = 36) Phenotype n (%) n (%) n (%) n (%) n(%) Extensive 5 (100.0) 5 (83.3) 2 (100.0) 23 (100.0) 35 (97.2)Metabolizer Poor 0 (0.0)  1 (16.7) 0 (0.0)  0 (0.0)  1 (2.8) Metabolizer^(a)Maximum Tolerated Dose is the last dose taken when the subject leftor completed the study. ^(b)This group included subjects who took two15-mg capsules/day as well as subjects who took one 30-mg capsule/day.^(c)This group included one subject whose MTD was 45 mg.

All except one subject were extensive metabolizers. Concentrations inplasma of DM increased between the visit on Day 15 and the final visitfor the 90-mg and 120-mg MTDs. A similar increase in concentration wasseen for the metabolite DX and for Q. Concentrations of DM, DX, and Q inplasma of extensive metabolizers at the final visit are summarized byMTD in Table 56.

TABLE 56 Drug MTD^(b) (mg) or Metabolite 30^(c) 60^(d) 90 120 Total(ng/mL) Statistic N = 5 N = 5 N = 2 N = 23 N = 35 DM n 3 5 2 23 33 Mean59.0 46.2 117.0 192.6 153.7 SD 30.28 67.38 44.47 98.93 106.01 Median67.4 1.5 117.0 178.0 144.5 Min/Max 25.4/84.2 0.0/150.2 85.5/148.448.7/388.5 0.0/388.5 DX n 3 5 2 23 33 Mean 70.7 65.4 88.4 146.6 123.9 SD48.49 67.38 34.83 96.88 91.94 Median 94.6 58.2 88.4 122.6 102.6 Min/Max14.9/102.6 0.0/135.6 63.8/113.0 53.2/417.9 0.0/417.9 Q n 3 5 2 23 33Mean 114.0 41.8 114.5 269.0 211.1 SD 48.75 66.72 70.00 176.88 175.28Median 137.0 0.0 114.5 211.0 164.0 Min/Max 58/147 0/153 65/164 74/6810/681 ^(a)One of the thirty-six subjects was a poor metabolizer.^(b)Maximum Tolerated Dose is the last dose taken when the subject leftor completed the study. ^(c)This group included subjects who took two15-mg capsules/day as well as subjects who took one 30-mg capsule/day.^(d)This group included one subject whose MTD was 45 mg.

For comparison, the poor metabolizer (MTD of 60 mg) had the followingconcentrations in plasma at the final visit: DM 126.4 ng/mL, DX 41.0ng/mL, and Q 165.0 ng/mL. Correlations between the concentration of DMin plasma with pain intensity ratings on Day 15, Day 29, and the finalvisit are summarized in Table 57 (extensive metabolizers only).

TABLE 57 Visit n^(b) Correlation Coefficient P-value Day 15 33 −0.34790.0473 Day 29 30 −0.1336 0.4817 Final Visit 33 −0.1487 0.4088 ^(a)One ofthe thirty-six subjects was a poor metabolizer. ^(b)Data were notavailable for all subjects.

There was a weak, negative correlation between concentration of DM inplasma and rating of pain intensity at Day 15 (coefficient of −0.3572)and negligible correlations at the other time points (≦−0.1487). The Day15 correlation was statistically significant (p=0.0473), but thecorrelations at Day 29 and the final visit were not (p≧0.4088). However,a weak or nonexistent correlation between concentrations of drug inplasma and pain ratings is a typical result in pharmacodynamic studiesof analgesics.

The safety results demonstrate that the combination of DM/Q, in the doserange from 30 mg DM/30 mg Q to 120 mg DM/120 mg Q, is safe and welltolerated in the treatment of subjects with pain associated withdiabetic peripheral neuropathy, and provide indications of efficacy inpain reduction.

The preferred embodiments have been described in connection withspecific embodiments thereof. It will be understood that it is capableof further modification, and this application is intended to cover anyvariations, uses, or adaptations of the invention following, in general,the principles of the invention and including such departures from thepresent disclosure as come within known or customary practices in theart to which the invention pertains and as may be applied to theessential features hereinbefore set forth, and as fall within the scopeof the invention and any equivalents thereof. All references citedherein, including but not limited to technical literature references andpatents, are hereby incorporated herein by reference in theirentireties.

What is claimed is:
 1. A method for treating traumatic brain injury, themethod comprising administering to a patient in need thereofdextromethorphan in combination with quinidine, wherein the amount ofdextromethorphan administered comprises from about 20 mg/day to about 60mg/day and wherein the amount of quinidine administered comprises fromabout 10 mg/day to about 30 mg/day with the proviso that theweight-to-weight ratio of dextromethorphan to quinidine is 1:0.75 orless of quinidine.
 2. The method of claim 1, wherein thedextromethorphan and the quinidine are administered as one combined doseper day.
 3. The method of claim 1, wherein the dextromethorphan and thequinidine are administered as at least two combined doses per day. 4.The method of claim 1, wherein the amount of quinidine administeredcomprises from about 20 mg/day to 30 mg/day.
 5. The method of claim 1,wherein the amount of dextromethorphan administered comprises from about40 mg/day to 60 mg/day.
 6. The method of claim 1, wherein at least oneof the quinidine and the dextromethorphan is in a form of apharmaceutically acceptable salt.
 7. The method of claim 1, wherein atleast one of the quinidine and the dextromethorphan is in a form of apharmaceutically acceptable salt selected from the group consisting ofsalts of free acids, inorganic salts, salts of sulfate, salts ofhydrochloride, and salts of hydrobromide.
 8. The method of claim 1,wherein about 20 mg quinidine sulfate is administered per day.
 9. Themethod of claim 1, wherein about 60 mg dextromethorphan hydrobromide isadministered per day.
 10. The method of claim 1 wherein thedextromethorphan and quinidine are administered in separate doses. 11.The method of claim 1 wherein the weight-to-weight ratio ofdextromethorphan to quinidine is 1:0.65 or less of quinidine.
 12. Themethod of claim 1, wherein about 40 mg dextromethorphan hydrobromide isadministered per day.
 13. The method of claim 1, wherein about 60 mg ofdextromethorphan and about 20 mg of quinidine is administered per day.14. The method of claim 1, wherein about 40 mg of dextromethorphan andabout 20 mg of quinidine is administered per day.
 15. The method ofclaim 1, wherein about 60 mg of dextromethorphan hydrobromide and about20 mg of quinidine sulfate is administered per day.
 16. The method ofclaim 1, wherein about 40 mg of dextromethorphan hydrobromide and about20 mg of quinidine sulfate is administered per day.